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Stem Cells and Cloning: Advances and Applications, pp 3-7; doi:10.2147/sccaa.s304887

There is numerous evidence for the presence of stem cells, which is important for the treatment of a wide variety of disease conditions. Stem cells have a great therapeutic effect on different degenerative diseases through the development of specialized cells. Embryonic stem (ES) cells are derived from preimplantation embryos, which have a natural karyotype. This cell has the capacity of proliferation indefinitely and undifferentiated. Stem cells are very crucial for the treatment of different chronic and degenerative diseases. For instance, stem cell clinical trials have been done for ischemic heart disease. Also, the olfactory cells for spinal cord lesions and human fetal pancreatic cells for diabetes mellitus are the other clinical importance of stem cell therapy. Extracellular matrix (ECM) and other environmental factors influence the fate and activity of stem cells.
Frontiers in Bioengineering and Biotechnology, Volume 9; doi:10.3389/fbioe.2021.644076

Editorial on the Research Topic Advanced Therapies for Cardiac Regeneration Cardiovascular diseases (CVDs) are the leading cause of death worldwide, accounting for ~18 million deaths annually (WHO data). The term CVD gathers a group of different disorders involving the heart, its constituent structures, and the blood vessels. Among CVDs, coronary heart disease and stroke are responsible for four out of five CVD-related deaths, and one third of these deaths occur prematurely in people aged 70 or younger. The progressive or sudden obstruction of the coronary arteries is responsible for the onset of myocardial infarction which initiates a detrimental cascade of events finally leading to heart failure. More in detail, heart failure results from the continuous remodeling of the scar tissue replacing the beating heart muscle in the infarcted region, and represents a chronic condition in which the heart muscle progressively loses its ability to pump enough blood to fulfill the needs of all the body's compartments. Heart failure thus represents the main cause of morbidity and mortality of myocardial infarcted patients in the long term. Within this context, cardiac tissue engineering/regenerative medicine (TERM) strategies could arise as cutting-edge therapies in the management of myocardial infarcted patients, opening the way to the possibility to replace the damaged heart tissue and recover its functionality. Such an approach could effectively represent a valid alternative to the gold standard heart transplantation, encompassing all issues related to donor shortage and the need for life-long administration of immunosuppressive therapies. Among other common cardiovascular diseases, we also recall valve heart diseases and cardiomyopathies. It must be highlighted the strong associations existing between different cardiovascular diseases, such as coronary heart disease and valvular heart disease, cardiomyopathy and heart failure. This observation indicates that a multiple regenerative medicine approach, which considers different diseases, could be an effective strategy in the management of CVDs. The Research Topic “Advanced Therapies for Cardiac Regeneration” aims at presenting a series of articles summarizing the latest research updates on cardiac TERM approaches which combine cells, biomaterials, hydrogels, tissue engineered scaffolds/patches and physico-chemical stimuli to achieve the ultimate goal of regenerating the injured heart tissue. The issue is comprised of 19 peer-reviewed manuscripts (nine reviews, two perspectives, seven original research articles, and one Brief Research Report) derived from the many fields involved in the topic, namely (bio)materials science and engineering, biology, biotechnology, and biomedical engineering. To better contextualize the Research Topic, the review by Montero et al. presents an in-depth overview of the specific characteristics of the myocardium that determine the needs and requirements cardiac TERM has to meet, with particular emphasis on heart tissue components, architecture and biophysical properties. The authors also briefly revise the key components required to design new cardiac TERM approaches, namely cells, materials, maturation stimuli, and scaffold fabrication techniques. Given the central role of biomaterials in the establishment of cardiac TERM therapies, Bar and Cohen focus their review on the current application of biomaterials in the field of cardiac regeneration, mainly discussing their use as forming materials for nano-carriers and matrices for cardiac regeneration induced by biomolecule release, injectable hydrogels for cell delivery, and cardiac patches. Further and more detailed insight on the use of specific biomaterials in cardiac TERM are provided by Cattelan et al. and Gonzalez De Torre et al., with particular emphasis on their application as hydrogel constituents. Being three-dimensional highly hydrated networks showing mechanical properties similar to soft tissues, hydrogels hold great promise in cardiac TERM. Cattelan et al. elucidate the promising properties of alginate in cardiac regeneration strategies and the outcomes of clinical trials in which this material has been tested to treat myocardial infarcted patients. An additional demonstration of the suitability of this material for cardiac TERM is provided by Bloise et al. who develop alginate hydrogels for the controlled release of immunomodulatory and reparative cytokines (anti-inflammatory interleukins 4/6/13 and colony-stimulating factor) to direct immune cell fate and control the wound healing process in the ischemic heart. The therapeutic ability of the proposed treatment has been proved in rat models by macrophage polarization toward healing and the improved global cardiac functionality. Differently, Gonzalez De Torre et al. discuss on the potential of elastin-based biomaterials as constituents of hydrogel scaffolds, injectable systems, or complex devices (e.g., heart valves, stents) to treat CVD-affected patients. In this regard, Fernàndez-Colino et al. investigate the use of elastin-like recombinamers as forming materials of small caliber compliant vascular grafts. The authors describe material processing into macroporous three-dimensional structures favoring cell homing, extracellular matrix (ECM) deposition and endothelium development, while exhibiting non-thrombogenicity and elastic properties mimicking the native elastin. Graft textile components are finely designed to confer proper suture retention, long-term structural stability, burst strength and compliance. The proper selection of the biomaterials used as constituents of cardiac scaffolds/patches/devices or hydrogels thus represents the first step toward the engineering of successful regenerative strategies for the management of CVD-affected patients. Indeed, biomaterials strongly affect the possibility to provide the resulting devices with proper biological signals and physical...
Roberto G Carbone, Simone Negrini, Giuseppe Murdaca, Francesco Puppo
Cardiology and Cardiovascular Medicine, Volume 05, pp 277-284; doi:10.26502/fccm.92920201

Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Several trials have been performed to evaluate benefit of stem cells transplantation to restore cardiac function in short- and long-term period after myocardial infarction. This concise review analyzes 15 clinical trials between 2005 and 2020 comprising 1372 patients (608 treated) and is aimed to: 1): assess percent increase in left ventricular ejection fraction (LVEF) and decrease in New York Heart Association (NYHA) class at 12 months after stem cells transplantation after acute myocardial infarction and 2) correlate LVEF percent increase with number of transfused stem cells. Nine trials reported a significant percent LVEF increase and NYHA class decrease at 12 months after bone marrow and peripheral blood stem cells transplantation correlating with transplanted cells number. Caution should be exercised in the evaluation of these results due to the different stem cells utilized, transplant protocols and endpoints, and the small number of patients treated in some studies.
Translational Andrology and Urology, Volume 10, pp 2617628-2612628; doi:10.21037/tau-20-1286

Erectile dysfunction (ED) impacts a significant portion of the aging male population. Standard treatments such as oral medications, intracavernosal injections, intraurethral suppositories, vacuum erection aids, and penile prosthesis placement have stood the test of time. Recently, there has been a growing interest in the concept of regenerative medicine with the goal of restoring or renewing functional tissue. Low intensity shock wave therapy (LiSWT) is one example of a regenerative therapy. A strong body of basic science data suggests that shockwaves, when applied to local tissue, will encourage blood vessel and nerve regeneration. Clinical evidence supports the use of LiSWT to treat conditions ranging from ischemic heart disease, musculoskeletal injuries, and even chronic non-healing wounds. LiSWT is also being used to treat male sexual dysfunction conditions such as Peyronie’s Disease and ED. The first studied application of LiSWT for ED was published in 2010. Since then multiple randomized, sham-controlled trials have sought to evaluate outcomes for this novel therapy in men with vasculogenic ED. Additionally, several meta-analyses are available with pooled data suggesting that LiSWT results in a significantly greater improvement in erectile function relative to sham-control. Despite these promising findings, the current body of literature is marred by significant heterogeneity relating to treatment protocols, patient populations, and follow-up duration. Further work is necessary to determine optimal device technologies, patient characteristics, and treatment duration prior to considering LiSWT as standard of care for men with ED.
Mehdi Hassanpour, Nasser Aghamohamadzade, Omid Cheraghi, Morteza Heidarzadeh,
Journal of Cardiovascular and Thoracic Research, Volume 12, pp 256-268; doi:10.34172/jcvtr.2020.44

Cardiovascular diseases (CVDs) are the leading cause of death globally. Because of the economic and social burden of acute myocardial infarction and its chronic consequences in surviving patients, understanding the pathophysiology of myocardial infarction injury is a major priority for cardiovascular research. MI is defined as cardiomyocytes death caused by an ischemic that resulted from the apoptosis, necrosis, necroptosis, and autophagy. The phases of normal repair following MI including inflammatory, proliferation, and maturation. Normal repair is slow and inefficient generally so that other treatments are required. Because of difficulties, outcomes, and backwashes of traditional therapies including coronary artery bypass grafting, balloon angioplasty, heart transplantation, and artificial heart operations, the novel strategy in the treatment of MI, cell therapy, was newly emerged. In cell therapy, a new population of cells has created that substitute with damaged cells. Different types of stem cell and progenitor cells have been shown to improve cardiac function through various mechanisms, including the formation of new myocytes, endothelial cells, and vascular smooth muscle cells. Bone marrow- and/or adipose tissue-derived mesenchymal stem cells, embryonic stem cells, autologous skeletal myoblasts, induced pluripotent stem cells, endothelial progenitor cells, cardiac progenitor cells and cardiac pericytes considered as a source for cell therapy. In this study, we focused on the point of view of the cell sources.
, Nasser Aghamohamadzade, Omid Cheraghi, Morteza Heidarzadeh,
Published: 24 November 2020
Cardiovascular diseases (CVDs) are the leading cause of death globally. Because of the economic and social burden of acute myocardial infarction and its chronic consequences in surviving patients, understanding the pathophysiology of myocardial infarction injury is a major priority for cardiovascular research. MI is defined as cardiomyocytes death caused by an ischemic that resulted from the apoptosis, necrosis, necroptosis, and autophagy. The phases of normal repair following MI including inflammatory, proliferation, and maturation. Normal repair is slow and inefficient generally so that other treatments are required. Because of difficulties, outcomes, and backwashes of traditional therapies including coronary artery bypass grafting, balloon angioplasty, heart transplantation, and artificial heart operations, the novel strategy in the treatment of MI, cell therapy, was newly emerged. In cell therapy, a new population of cells has created that substitute with damaged cells. Different types of stem cell and progenitor cells have been shown to improve cardiac function through various mechanisms, including the formation of new myocytes, endothelial cells, and vascular smooth muscle cells. Bone marrow- and/or adipose tissue-derived mesenchymal stem cells, embryonic stem cells, autologous skeletal myoblasts, induced pluripotent stem cells, endothelial progenitor cells, cardiac progenitor cells and cardiac pericytes considered as a source for cell therapy. In this study, we focused on the point of view of the cell sources.
Kristin C. Marr, Mph Jonathan Simkin, Andrea C. Lo, Joseph M. Connors, Md Mph Alina S. Gerrie, Mdmph Diego Villa, Msc Ciara L. Freeman, MBChB David W. Scott, Bmbs Greg Hapgood, Mdmph Laurie H. Sehn, et al.
Published: 5 November 2020
Blood, Volume 136, pp 18-19; doi:10.1182/blood-2020-136454

INTRODUCTION Adolescents and young adult (AYA) survivors of Hodgkin lymphoma (HL) are potentially at increased risk of cardiovascular (CV) disease due to anthracycline exposure, in addition to use of mediastinal radiotherapy (RT). Although the risk has been well described in the pediatric age-group, the impact in the AYA population has been less well characterized. Capturing the incidence of these late effects is challenging given that events can occur more than a decade after therapy completion. Using population-based administrative data, we evaluated the incidence of CV disease (combined heart failure (HF) and ischemic heart disease (IHD)) in a cohort of AYA survivors treated for classical HL (cHL) using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or equivalent chemotherapy. METHODS Patients with cHL aged 16-39 years (y), diagnosed between 1992-2013 and treated with an ABVD or equivalent therapy, were identified in the BC Cancer Lymphoid Cancer Database. Patients must have survived to an Index Date defined as 2 y from most recent HL event (primary diagnosis or if applicable, most recent relapse) and have had a minimum follow-up of 1 y beyond their Index Date. Patients were excluded if they had history of prior malignancy or HIV positivity. Limited stage disease was defined as stage IA, IB or IIA and absence of bulky disease (≥10cm); all others had advanced stage disease. Cases were linked with population-based databases of BC Cancer Registry; BC Radiation Oncology Database; and BC Ministry of Health (MOH) Chronic Disease Registry (CDR) that captures all BC residents registered with medical service plan coverage during the study period. The outcome variables, including HF and IHD, were defined by the BC MOH CDR using Standardized Case Definitions. To focus on late onset CV complications, only events that occurred after the Index Date were included in the analysis. A 10:1 individually-matched control population was identified from the CDR based on age, sex, and health authority region on the Index Date of the matched case. Controls were excluded if they had a pre-existing malignancy, HF, or IHD prior to the study window. Individual outcomes were collected from the Index Date of the matched case until December 31, 2015 or until an individual was censored due to loss to follow-up or death. Kaplan Meier (K-M) methodology and log-rank test was used to estimate cumulative incidence. A competing risk regression analysis was used to evaluate relative risk (RR) and p-values less than 0.05 were considered significant. RESULTS With a median follow-up time of 11 y (range 3-24 y) from most recent HL event, 764 AYA 2-y survivors were identified, aged 20 to 61 y (median 38 y) at the end of study period. The proportion of limited and advanced stage disease was 34.2% and 65.6%, respectively; and 49.9% were male. Eighty-eight patients (11.5%) had relapsed disease; eighty-six (11.3%) underwent high dose chemotherapy and autologous stem cell transplantation as part of their salvage therapy. In total, 268 patients (36.4%) were treated with mediastinal RT for primary therapy or for relapsed disease. Fifty-three percent received cumulative anthracycline dose ≥300 mg/m2. Survivors had a 3-fold increased risk of CV disease relative to controls (p<0.0001). The onset of CV disease in survivors occurred at median of 11.7 y after most recent treatment (range 2.2-19.2 y), and at a median age of 44.3 y (range 21 - 58 y). At 15 y, the estimated cumulative incidence of CV disease was 6.3% in survivors compared to 2.3% in controls (Figure A). In the 496 survivors that received chemotherapy only, the incidence of CV disease at 15 y was 4.6% vs 2.3% in controls, and those that received anthracyclines and mediastinal RT had significantly higher incidence at 8.6% (Figure B). The increase in risk was greatest for a diagnosis of HF (RR 6.92, p<0.0001): at 15 y, the cumulative incidence of HF was 2.2% vs 0.6% in controls. The RR of IHD was 2.63 (p<0.0001) with incidence of 5.1% in cases compared to 1.8% in controls. CONCLUSION Similar to the pediatric population, AYA cHL survivors are at increased risk of both HF and IHD after completion of treatment. The majority of patients had received ABVD alone and had a lower incidence of CV disease at 15 y when compared to those that received treatment that included mediastinal RT. These results will inform counseling regarding risk factor modification and aid in the development of surveillance guidelines for AYA survivors. Disclosures Gerrie: Sandoz: Consultancy; Roche: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Scott:NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding. Sehn:AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck:...
Laura A. Scrimgeour, Brittany A. Potz, Ahmad Aboul Gheit, Yuhong Liu, Guangbin Shi, Melissa Pfeiffer, Bonnie J. Colantuono, Neel R. Sodha, M. Ruhul Abid,
Published: 11 September 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0238879

Mesenchymal stem cell-derived extracellular vesicles (EVs) appear to be a very exciting treatment option for heart disease. Here, we used a swine model of chronic myocardial ischemia to evaluate the efficacy of a less-invasive method of injection of EVs via a peripheral intravenous route. Sixteen Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex (LCx) artery at age 11 weeks to induce chronic myocardial ischemia. Two weeks later, they were divided into two groups: control (CON; n = 8), and intravenous injection of EVs (EVIV; n = 8). At 18 weeks of age, animals underwent final analysis and euthanasia. The chronically ischemic myocardium (LCx territory) was harvested for analysis. Intravenous injection (IV) of EVs induced several pro-angiogenic markers such as MAPK, JNK but not Akt. Whereas IV injections of EVs decreased VEGFR2 expression and inhibited apoptotic signaling (caspase 3), they increased expression of VEGFR1 that is believed to be anti-angiogenic. Injection of EVs did not result in an increase in vessel density and blood flow when compared to the control group. Although IV injection of EVs upregulated several pro-angiogenic signaling pathways, it failed to induce changes in vascular density in the chronically ischemic myocardium. Thus, a lack of increase in vascular density at the doses tested failed to elicit a functional response in ischemic myocardium.
Angela C Castellanos, Bryon A Tompkins, Makoto Natsumeda, Victoria Florea, Monisha Banerjee, Jose Rodriguez, Marcos Rosado, Kristalenia Valasaki, Lauro Takeuchi, Sohil Desai, et al.
Circulation Research, Volume 127; doi:10.1161/res.127.suppl_1.471

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition involving multiple comorbidities. Phenotypic classification of HFpEF associated with chronic kidney disease (CKD) manifests worse outcomes, compared to other HFpEF phenotypes. Few treatments improve morbidity and mortality in HFpEF. Stem cell therapy promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that allogeneic stem cell treatment ameliorates HFpEF in a large animal model of CKD. Methods: Yorkshire pigs (n=26) underwent 5/6 embolization-mediated nephrectomy and 4-weeks later received either: allogeneic mesenchymal stem cells (MSCs) (10х10 6 ), Kidney stem cells (KSC; 10х10 6 ), combination (ACCT; MSC+KSC; 1:1 ratio [5х10 6 each]), or placebo (n=6-7/ group). Cell therapy was delivered via the patent renal artery of the remnant kidney. RNAsec analysis compared placebo and ACCT groups. Results: Mean arterial pressure increased significantly in the placebo- (21.89±6.05 mmHg, p-6 , NES = -2.32) in ACCT. Consistent with these results, there was a downregulation of canonical drivers of tubular damage and regeneration, including SOX9 (-2.39 fold, p=0.0004) and apoptosis of kidney cell types (-24.89 fold, p=0.004), including podocytes (-2.065 fold, p=0.04) with ACCT. ACCT administration also downregulated genes related to oxidative stress (-4.6 fold, p Conclusion: Intra-renal artery allogeneic cell therapy was safe. Beneficial effects were observed in the ACCT and MSC groups in the kidney and heart. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.
, , , , Daniela Lobenwein, Martina Mitrovic, Agnes Mayr, Markus Theurl, Michael Schreinlechner, Matthias Pamminger, et al.
Published: 30 May 2020
Trials, Volume 21; doi:10.1186/s13063-020-04369-0

Background Coronary artery diseases (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodeling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy. Shockwave Therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function. Methods/design In this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min Walk Test distance, improvement of symptoms and assessment of quality of life. Discussion This study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure. Trial registration, ID: NCT03859466. Registered on 1 March 2019.
D. Kent Arrell, , , Atta Behfar, Andre Terzic
Published: 12 March 2020
npj Regenerative Medicine, Volume 5; doi:10.1038/s41536-020-0091-6

Cardiopoietic stem cells have reached advanced clinical testing for ischemic heart failure. To profile their molecular influence on recipient hearts, systems proteomics was here applied in a chronic model of infarction randomized with and without human cardiopoietic stem cell treatment. Multidimensional label-free tandem mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell therapy non-stochastically reversed a majority of infarction-provoked changes, remediating 85% of disease-affected protein clusters. Pathway and network analysis decoded functional reorganization, distinguished by prioritization of vasculogenesis, cardiac development, organ regeneration, and differentiation. Subproteome restoration nullified adverse ischemic effects, validated by echo-/electro-cardiographic documentation of improved cardiac chamber size, reduced QT prolongation and augmented ejection fraction post-cell therapy. Collectively, cardiopoietic stem cell intervention transitioned infarcted hearts from a cardiomyopathic trajectory towards pre-disease. Systems proteomics thus offers utility to delineate and interpret complex molecular regenerative outcomes.
, , Erik Jørgensen, Steffen Helqvist, , Michael Ng, Kishore Bhakoo,
Published: 14 November 2019
Stem Cells International, Volume 2019, pp 1-10; doi:10.1155/2019/2754927

Background. While regenerative stem cell therapy for ischemic heart disease has moved into phase 3 studies, little is still known about retention and migration of cell posttransplantation. In human studies, the ability to track transplanted cells has been limited to labeling with radioisotopes and tracking using nuclear imaging. This method is limited by low resolution and short half-lives of available radioisotopes. Longitudinal tracking using magnetic resonance imaging (MRI) of myocardial injected cells labeled with iron oxide nanoparticles has shown promising results in numerous preclinical studies but has yet to be evaluated in human studies. We aimed to evaluate MRI tracking of mesenchymal stromal cells (MSCs) labeled with ultrasmall paramagnetic iron oxide (USPIO) nanoparticles after intramyocardial transplantation in patients with ischemic heart disease (IHD). Methods. Five no-option patients with chronic symptomatic IHD underwent NOGA-guided intramyocardial transplantation of USPIO-labeled MSCs. Serial MRI scans were performed to track labeled cells both visually and using semiautomated T2 ∗ relaxation time analysis. For safety, we followed symptoms, quality of life, and myocardial function for 6 months. Results. USPIO-labeled MSCs were tracked for up to 14 days after transplantation at injection sites both visually and using semiautomated regional T2 ∗ relaxation time analysis. Labeling of MSCs did not impair long-term safety of treatment. Conclusion. This was a first-in-man clinical experience aimed at evaluating the utility of MRI tracking of USPIO-labeled bone marrow-derived autologous MSCs after intramyocardial injection in patients with chronic IHD. The treatment was safe, and cells were detectable at injection sites up to 14 days after transplantation. Further studies are needed to clarify if MSCs migrate out of the injection area into other areas of the myocardium or if injected cells are washed out into the peripheral circulation. The trial is registered with NCT03651791.
, Anders Bruun Mathiasen, Steffen Helqvist, Erik Jørgensen, Mandana Haack-Sørensen, , Jens Kastrup
Published: 12 November 2019
Journal of Translational Medicine, Volume 17, pp 360-9; doi:10.1186/s12967-019-2110-1

Background Stem cell therapy is investigated as a treatment option for patients with ischemic heart disease. In this study, long-term safety and efficacy of autologous intra-myocardial injections of adipose-derived stromal cells (ASCs) was studied in patients with refractory angina. Methods Sixty patients with coronary artery stenosis and preserved left ventricular ejection fraction were 2:1 randomised to intramyocardial injections of ASCs or saline and followed for 3 years. Results For patients in the ASC group, the bicycle exercise time and the exercise performance in watt were un-changed (383 ± 30 s to 370 ± 44 s, P = 0.052 and 81 ± 6 to 78 ± 10, P = 0.123, respectively), but the performance in METs was reduced significantly (4.2 ± 0.3 to 4.0 ± 0.4, P = 0.027) during the follow-up period. However, in the same period, there was in the placebo group a significant decline in bicycle exercise time (437 ± 53 s to 383 ± 58 s, P = 0.001), the exercise performance measured in watt (87 ± 12 W to 80 ± 12 W, P = 0.019) and in METs (4.5 ± 0.4 to 4.1 ± 0.4, P = 0.002). Moreover, angina measured as CCS class was significantly reduced in the ASC group but not in the placebo group (2.5 ± 0.9 to 1.8 ± 1.2, P = 0.002 and 2.5 ± 0.8 to 2.1 ± 1.3, P = 0.186, respectively). However, no significant change was observed between the two groups. Conclusions Patients receiving ASCs had improved cardiac symptoms and unchanged exercise capacity, in opposition to deterioration in the placebo group. Trial registration Identifier: NCT01449032. Registered 7 October 2011—Retrospectively registered,
, Anders Bruun Mathiasen, Naja Dam Mygind, Niels Groove Vejlstrup, Jens Kastrup
Published: 8 November 2019
Cell Transplantation, Volume 28, pp 1700-1708; doi:10.1177/0963689719883592

Adipose-derived stromal cell (ASC) therapy is currently investigated as a new treatment option for patients with ischemic heart disease (IHD). The aim of this study was to evaluate the effect of ASC therapy in patients with chronic IHD measuring myocardial perfusion and cardiac function using cardiac magnetic resonance imaging (CMRI). Patients were included in MyStromalCell trial, a phase II, randomized, double-blinded, placebo-controlled study investigated the effect of ASCs in patients with chronic IHD with preserved left ventricular ejection fraction (LVEF). In total, 41 of 60 patients underwent cine, late enhancement, rest and stress imaging with CMRI. There was a non-significant difference between stress and rest values in maximal signal intensity, a measure of myocardial perfusion, from baseline to follow-up comparing placebo with ASC group (-52.52 ± 88.61 and 3.05 ± 63.17, p = 0.061, respectively). LVEF, myocardial mass, stroke volume, left ventricle end-diastolic volume and end-systolic volume changed non-significantly (-0.5 ± 4.7%, -3.5 ± 13.1 g, -0.7 ± 8.6 mL, 1.9 ± 25.1 mL and 2.6 ± 16.5 mL, respectively) in the placebo group and in the ASC group (0.7 ± 8.6%, 0.9 ± 10.8 g, -0.3 ± 26.1 mL, -3.0 ± 31.5 mL and -2.7 ± 20.4 mL, respectively) from baseline to 6 months follow-up. The amount of scar tissue was unchanged in the placebo group by 0.0 ± 1.6 g, p = 1.0 and in the ASC group with -0.3 ± 2.3 g, p = 0.540. There was no difference between the groups. There was a non-significant trend toward increased myocardial perfusion but no significant changes in functional parameters or amount of scar tissue in patients treated with ASCs compared with patients allocated into the placebo group.
A A Qayyum, A B Mathiasen, S Helqvist, E Joergensen, M H Haack-Soerensen, A Ekblond, J Kastrup
European Heart Journal, Volume 40; doi:10.1093/eurheartj/ehz746.0343

Background Improvements in medical and interventional therapies have transformed ischemic heart disease into a chronic illness for lot of patients. The disease is in progress and by time patients suffer from cardiac symptoms, reduced work capacity and decline in quality of life. Stem cell therapy is investigated as a treatment option for these patients. Purpose In this study, long-term safety and efficacy of autologous intra-myocardial injections of adipose-derived stromal cells (ASCs) were studied in patients with refractory angina. Methods Sixty patients were double-blinded 2:1 randomised to ASC or saline injections and followed for three years. The patients had significant angina due to ≥1 coronary artery stenosis but preserved left ventricular ejection fraction. ASCs were obtained from abdomen, ex vivo culture expanded and VEGF-A165 stimulated before delivery into the ischemic myocardium. Results The cardiac symptoms, CCS and NYHA classification, were significantly reduced in the ASC group during the three years follow-up period (2.5±0.9 to 1.8±1.2, P=0.002 and 2.4±0.6 to 2.2±0.8, P=0.007, respectively). However, no significant change was observed in CCS or NYHA in the placebo group during the follow-up period (2.5±0.8 to 2.1±1.3, P=0.186 and 2.7±0.6 to 2.4±0.8, P=0.314, respectively). Moreover, the number of weekly angina attacks reported was significantly reduced in the ASC group (P=0.017), but not in the placebo group (P=0.425). For patients in the ASC group, the bicycle exercise time (383±30s to 370±44s, P=0.052) and the exercise performance in watt were un-changed (81±6 to 78±10, P=0.123), but the performance in METs was reduced significantly (4.2±0.3 to 4.0±0.4, P=0.027) during the follow-up period. At the same time in the placebo group, there was a significant decline in bicycle exercise time (437±53s to 383±58s, P=0.001), the exercise performance measured in watt (87±12 watt to 80±12 watt, P=0.019) and in METs (4.5±0.4 to 4.1±0.4, P=0.002). In both groups, significant improved quality-of-life, angina stability, angina frequency and physical limitation score was observed but not for overall satisfaction score. Conclusion Patients receiving ASCs had improved cardiac symptoms during the three years follow-up period, which was not the case for patients in the placebo group. Moreover, patients receiving ASCs had unchanged exercise capacity, in opposition to deterioration in the placebo group. Acknowledgement/Funding Arvid Nilssons Foundation; Rigshospitalets Research Foundation; Aase and Ejnar Danielsens Foundation
Published: 31 January 2019
BMC Cardiovascular Disorders, Volume 19, pp 1-9; doi:10.1186/s12872-019-1011-9

Heart failure (HF) is a major chronic illness and results in high morbidity and mortality. The most frequent cause of HF with reduced ejection fraction (HFREF) is coronary artery disease (CAD). Although revascularisation of ischemic myocardium lead to improvements in myocardial contractility and systolic function, it cannnot restore the viability of the already necrotic myocardium. The aim of our prospective randomised study is to assess the efficacy of the retrograde application of non-selected bone marrow autologous cells concentrate (BMAC) in patients with HFREF of ischemic aetiology. The evaluated preparation is concentrated BMAC, obtained using Harvest SmartPReP2 (Harvest Technologies, Plymouth, MA, USA). The study population will be a total of 40 patients with established CAD, systolic dysfunction with LV EF of ≤40% and HF in the NYHA class 3. Patients have been on standard HF therapy for 3 months and in a stabilised state for at least 1 month, before enrolling in the clinical study. Patients will be randomised 1:1 to either retrograde BMAC administration via coronary sinus or standard HF therapy. The primary end-points (left ventricular end-systolic and end-diastolic diameters [LVESd/EDd] and volumes [LVESV/EDV] and left ventricular ejection fraction [LV EF]) will be assessed by magnetic resonance imaging. The follow-up period will be 12 month. The application of bone marrow stem cells into affected areas of the myocardium seems to be a promising treatment of ischemic cardiomyopathy. The Harvest BMAC contains the entire population of nuclear cells from bone marrow aspirates together with platelets. The presence of both platelets and additional granulocytes can have a positive effect on the neovascularisation potential of the resulting concentrate. Our assumption is that retrograde administration on non-selected BMAC via coronary sinus, due to the content of platelets and growth factors, might improve left ventricular function and parameters compared to standard HF therapy. Furthermore, it will be associated with improved exercise tolerance in the six-minute corridor walk test and an improvement in the life quality of patients without increasing the incidence of severe ventricular arrythmias. (; ; NCT03372954).
Linhui Shi, Longqiang Ye, Panpan Liu, Danqin Liu, Gongjie Ye, Jiahong Chen,
Published: 11 January 2019
Molecular Medicine Reports, Volume 19, pp 2397-2406; doi:10.3892/mmr.2019.9847

Mesenchymal stem cells (MSCs) have exhibited great potential in the therapy of cardiovascular disease. However, the application of MSCs is hampered by apoptosis, which reduces the number of cells in the host cardiac microenvironment. Ulinastatin (UTI), a broad‑spectrum protease inhibitor that can be purified from human urine, has attracted attention for its protective effects through its immunomodulatory and anti‑inflammatory properties. The present study aimed to evaluate the effects of UTI on serum deprivation‑induced apoptosis of MSCs and investigate its molecular mechanisms. Cell viability was determined by the MTT assay. Apoptosis was assessed by flow cytometric analysis with Annexin V/propidium iodide staining. The protein levels of cleaved caspase‑3, B‑cell lymphoma‑2 (Bcl‑2) family proteins, total‑Akt and phospho‑Akt were evaluated by western blot. The results of the present study demonstrated that UTI exhibited a protective effect in serum deprived MSCs, as indicated by increased cell viability, and a reduction in the rate of apoptosis and caspase‑3 activation. In addition, treatment with UTI significantly decreased the expression levels of Bcl‑2, Bcl‑extra large and Bcl‑associated X protein. Furthermore, activation of the Akt signaling pathway was involved in the UTI‑induced anti‑apoptotic effects. The present findings indicated that UTI is able to promote the survival of MSCs under serum deprivation conditions. The present study may be helpful in improving the therapeutic efficacy of MSC transplantation used to cure chronic ischemic heart disease.
Melanie Villanueva, Connor Michie, Sandrine Parent, Georges N Kanaan, Ghazaleh Rafatian, Pushpinder Kanda, Bin Ye, Wenbin Liang, Mary-Ellen Harper,
Published: 1 January 2019
Theranostics, Volume 9, pp 5720-5730; doi:10.7150/thno.36639

Decades of work have shown that diabetes increases the risk of heart disease and worsens clinical outcomes after myocardial infarction. Because diabetes is an absolute contraindication to heart transplant, cell therapy is increasingly being explored as a means of improving heart function for these patients with very few other options. Given that hyperglycemia promotes the generation of toxic metabolites, the influence of the key detoxification enzyme glyoxalase 1 (Glo1) on chronic hyperglycemia induced heart explant-derived cell (EDC) dysfunction was investigated. Methods: EDCs were cultured from wild type C57Bl/6 or Glo1 over-expressing transgenic mice 2 months after treatment with the pancreatic beta cell toxin streptozotocin or vehicle. The effects of Glo1 overexpression was evaluated using in vitro and in vivo models of myocardial ischemia. Results: Chronic hyperglycemia reduced overall culture yields and increased the reactive dicarbonyl cell burden within EDCs. These intrinsic cell changes reduced the angiogenic potential and production of pro-healing exosomes while promoting senescence and slowing proliferation. Compared to intra-myocardial injection of normoglycemic cells, chronic hyperglycemia attenuated cell-mediated improvements in myocardial function and reduced the ability of transplanted cells to promote new blood vessel and cardiomyocyte growth. In contrast, Glo1 overexpression decreased oxidative damage while restoring both cell culture yields and EDC-mediated repair of ischemic myocardium. The latter was associated with enhanced production of pro-healing extracellular vesicles by Glo1 cells without altering the pro-healing microRNA cargo within. Conclusions: Chronic hyperglycemia decreases the regenerative performance of EDCs. Overexpression of Glo1 reduces dicarbonyl stress and prevents chronic hyperglycemia-induced dysfunction by rejuvenating the production of pro-healing extracellular vesicles.
Qian Wang, Yaning Zhang, Bing Yue, Yu Zhang, Changchuan Jiang, Stuthi Perimbeti, Michael J. Mauro
Published: 29 November 2018
Blood, Volume 132, pp 1737-1737; doi:10.1182/blood-2018-99-110408

Background: Since the US Food and Drug Administration (FDA) approved the first BCR-ABL1-targeted tyrosine kinase inhibitor (TKI) imatinib in 2002 as the first line therapy1, chronic phase chronic myeloid leukemia (CML-CP), once a uniformly fatal disease, now has become a disease that is controlled in >90% patients2. Conventional treatment for CML before TKIs included hydroxyurea, interferon alpha with or without cytarabine, busulfan, as well as stem cell transplantation3. Currently, there are five TKIs approved by FDA for chronic-phase CML treatment: imatinib, nilotinib, dasatinib, bosutinib, and ponatinib4.Studies have suggested that CML patients have higher baseline cardiovascular comorbidities than general US population5. Moreover, TKIs, especially later generation, are associated with cardiovascular toxicities including myocardial infarction, ischemic heart disease, cerebrovascular disease, peripheral arterial disease, QT prolongation, hypertension, and venous thrombosis1,4,6-9. As patients may need life-long (or minimum of several years') therapy, the cardiovascular safety profile of TKI treatment warrants utmost attention. Thus, we examined the effect of TKIs on cardiovascular mortality using the SEER database. Methods: Data were extracted from the Surveillance, Epidemiology and End Results (SEER) 18 program 1992-2004. Cardiovascular diseases were defined as diseases of the heart, hypertension, cerebrovascular disease, atherosclerosis, aortic aneurysm and dissection, and other disease of arteries, arterioles, and capillaries. Time of diagnosis between 1992-2002 was defined as pre-TKI era and 2003-2014 as TKI era. Patients had BCR/ABL negative CML or any other cancer before CML were excluded. T-test and chi-square test were used to analyze the baseline characteristics. Multivariable Cox proportional hazards regression was used to calculate the hazard ratio (HR). Sub-distribution hazard ratios (SHRs) for cardiovascular disease (CVD) specific mortality were calculated by using Fine and Gray competing-risks model. All above statistical tests were performed assuming a 2-sided alpha of 0.05 by using SAS 9.4. CVD standard mortality ratio (SMR) and absolute excess risk (AER) were calculated by using SEER*Stat 8.3.5 software MP-SIR Matrix comparing to the total U.S. population (1969-2016 Counties). Results: A total of 10,502 patients were included (Table 1). Table 2 shows that as expected, increased age was associated with higher CVD mortality. Females had a 20% decreased risk of overall CVD mortality compared to males. Notably, those diagnosed in the TKI era had better cardiovascular outcome than the pre-TKI diagnosis, HR=0.78 (95%CI: 0.64-0.94), which was also illustrated in Figure 1. In the adjusted model (Table 3), the significantly decreased mortality in the TKI era was mostly observed at 10-year follow up and among the youngest age group 15-44 years. The 10-year cardiovascular mortality also differed by gender, especially after age 54...
Theresa H.M. Keegan, Lori S Muffly, Qian Li, Elysia Alvarez, Ann M Brunson, Marcio Malogolowkin, Ted Wun
Published: 29 November 2018
Blood, Volume 132, pp 839-839; doi:10.1182/blood-2018-99-111553

Introduction: Adolescent and young adult (AYA) cancer survivors are at an increased risk of developing subsequent medical problems, including asthma/chronic obstructive pulmonary disorder, cardiovascular disease, diabetes and second cancers. However, few population-based studies have focused on these risks in AYAs with NHL, ALL or AML or considered whether the occurrence of these and other medical conditions differ by sociodemographic factors. Methods: Data for patients aged 15-39 when diagnosed with NHL (n=4,459), ALL (n=1,100) and AML (n=1,107) during 1996-2012 and surviving a minimum of 2 years were obtained from the California Cancer Registry and followed in California hospital discharge databases. Discharge diagnoses were used to classify medical conditions as cardiac (hypertensive disease, ischemic heart disease, other heart disease), neurologic (stroke, seizure), endocrine (hypothyroidism, diabetes, ovarian/testicular dysfunction, other metabolic diseases), respiratory (asthma, chronic obstructive pulmonary disease), renal (chronic kidney disease, hemodialysis, kidney transplant), liver (chronic liver disease, pancreatitis, cirrhosis, liver transplant), and avascular necrosis. Second cancers were obtained from the cancer registry. We estimated the cumulative incidence (CMI) of developing each condition 10-years after diagnosis, accounting for death as a competing risk. We determined the impact of race/ethnicity, neighborhood socioeconomic status (SES), health insurance status and stem cell transplant (SCT) on the occurrence of each medical condition after adjusting for other demographic and clinical factors using multivariable Cox proportional hazards regression. Results: The most common medical conditions among AYA survivors at 10-years were cardiac (CMI NHL: 11.6%; ALL= 20.5%; AML= 18.2%), endocrine (CMI NHL: 18.6%; ALL= 33.0%; AML= 25.9%) and respiratory (CMI NHL: 5.1%; ALL= 7.7%; AML= 6.8%) diseases. Avascular necrosis had the highest CMI in ALL patients (CMI NHL: 1.2%; ALL= 8.7%; AML= 2.5%). Neurologic (CMI NHL: 2.1%; ALL= 4.5%; AML= 4.9%) and liver (CMI NHL: 2.0%; ALL= 5.6%; AML= 4.4%) were more common in survivors of ALL and AML than NHL. Second cancers (2.3-2.5%) and renal diseases (2.2-3.5%) were less common at 10-years. NHL survivors with advanced stage disease had a higher incidence of all medical conditions, except second cancers. Chemotherapy was associated with a higher CMI of cardiac and endocrine conditions among NHL survivors; these associations could not be assessed in ALL and AML patients as nearly all patients received chemotherapy. Initial radiation therapy was not associated with a higher CMI of medical conditions in NHL or ALL survivors, but was associated with a higher CMI of respiratory, renal and endocrine diseases in AML survivors. In multivariable models, public or no insurance (vs private) was associated with a higher risk of most medical conditions in NHL and ALL survivors, but not AML survivors (Table). The risk of developing medical conditions varied by race/ethnicity, with Hispanics ALL survivors (vs non-Hispanic whites) at a higher risk of cardiac, renal, liver, endocrine, second cancers and neurologic diseases and black AML survivors at a higher risk of all medical conditions, except endocrine diseases. AYAs with NHL who resided in lower SES neighborhoods were at a higher risk for developing cardiac, respiratory and endocrine diseases; AML survivors in lower SES neighborhoods had a higher risk of respiratory diseases. Across all cancers, AYAs undergoing a SCT were at a higher risk of most medical conditions. Conclusion: This study found that sociodemographic factors were associated with the risk of developing medical conditions in AYA NHL, ALL and AML survivors. As expected, the risk of medical conditions varied by cancer type and treatment, with those undergoing SCT having a higher risk of medical conditions regardless of cancer type. NHL and ALL survivors who were uninsured or publicly insured were at a consistently higher risk of developing medical conditions, as were Hispanic ALL survivors and Black AML survivors. Our findings highlight the higher burden of medical conditions in subgroups of cancer survivors that may relate to reduced access to preventive care, early detection/intervention and long-term surveillance. Disclosures Muffly: Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding.
, , M. Rezaa Mohammadi, Mansi Bharat Parekh, Abhijit Achyut Gurjarpadhye, , Viktors Dubniks, Jonathan R.T. Lakey,
Published: 1 October 2018
Cytokine & Growth Factor Reviews, Volume 43, pp 54-68; doi:10.1016/j.cytogfr.2018.08.003

Cytokine therapies have emerged during the past decade as promising noninvasive treatments for heart disease. In general, current drug treatments are directed towards symptom control and prevention of disease progression; however, many agents also produce cause side effects that alter quality of life. Cytokine based therapies have the potential to reduce post-infarct heart failure and chronic ischemia by stimulating the proliferation and differentiation of endothelial cells and bone marrow hematopoietic stem cells and mobilizing these cells toward ischemic tissue. In turn, these mobilized cell populations contribute to myocardial regeneration. In contrast, over-expression of several cytokines has been linked to a variety of heart diseases; thus, therapies targeting and monitoring these cytokines are of great interest. Here we summarize results from clinical studies on cytokines as therapeutic agents or therapeutic targets in the treatment for heart disease as well as cytokines involved in the evolution of heart disease.
Roberto Bolli, Joshua M. Hare, Keith L. March, , James T. Willerson, Emerson C. Perin, Phillip C. Yang, Timothy D. Henry, Jay H. Traverse, Raul D. Mitrani, et al.
Circulation Research, Volume 122, pp 1703-1715; doi:10.1161/circresaha.118.312978

Autologous bone marrow (BM) mesenchymal stem cells (MSCs) and c-kit cardiac progenitor cells (CPCs) are two promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans regarding the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. CONCERT-HF (Combination Of meseNchymal and c-kit Cardiac stEm cells as Regenerative Therapy for Heart Failure) is a Phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). Using a randomized, double-blinded, placebo-controlled, multi-center, multi-treatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs + CPCs in this population alleviates left ventricular (LV) remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The four-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (Stage 1) and 144 in the main trial (Stage 2). Stage 1 is complete and Stage 2 is currently randomizing patients from seven centers across the US. CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. : NCT02501811.
Eleonora Cianflone, Iolanda Aquila, Mariangela Scalise, , , ,
Published: 18 April 2018
Cell Cycle, Volume 17, pp 927-946; doi:10.1080/15384101.2018.1464852

Ischemic Heart Disease (IHD) remains the developed world's number one killer. The improved survival from Acute Myocardial Infarction (AMI) and the progressive aging of western population brought to an increased incidence of chronic Heart Failure (HF), which assumed epidemic proportions nowadays. Except for heart transplantation, all treatments for HF should be considered palliative because none of the current therapy can reverse myocardial degeneration responsible for HF syndrome. To stop the HF epidemic will ultimately require protocols to reduce the progressive cardiomyocyte (CM) loss and to foster their regeneration. It is now generally accepted that mammalian CMs renew throughout life. However, this endogenous regenerative reservoir is insufficient to repair the extensive damage produced by AMI/IHD while the source and degree of CM turnover remains strongly disputed. Independent groups have convincingly shown that the adult myocardium harbors bona-fide tissue specific cardiac stem cells (CSCs). Unfortunately, recent reports have challenged the identity and the endogenous myogenic capacity of the c-kit expressing CSCs. This has hampered progress and unless this conflict is settled, clinical tests of repair/regenerative protocols are unlikely to provide convincing answers about their clinical potential. Here we review recent data that have eventually clarified the specific phenotypic identity of true multipotent CSCs. These cells when coaxed by embryonic cardiac morphogens undergo a precisely orchestrated myogenic commitment process robustly generating bona fide functional cardiomyocytes. These data should set the path for the revival of further investigation untangling the regenerative biology of adult CSCs to harness their potential for HF prevention and treatment.
Published: 5 April 2018
Shockwave Medicine, Volume 6, pp 87-101; doi:10.1159/000485064

Despite the availability of state-of-the-art treatment, there are still a significant number of patients with severe and diffuse atherosclerotic-obstructive coronary artery disease who are not only unsuitable for treatment of coronary artery disease, but also poor responders to medications. Additionally, atherosclerotic peripheral artery occlusive disease (PAOD) that affects 8-12% of Americans >65 years of age is associated with a major decline in functional status, increased myocardial infarction, and stroke rates as well as increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. Cell therapy has appeared as a potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function as well as for PAOD. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results, that is, with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These issues raise the need for developing an alternative strategic management with safety and efficacy for those of cardiovascular disease patients who are refractory to conventional therapy. Growing data have demonstrated that low energy of extracorporeal shockwave therapy (ESWT) dramatically improved chronic ischemic heart disease and hind limb ischemia, and preserving neurological function after ischemic stroke mainly through enhancing angiogenesis, upregulating the expression of stromal cell-derived factor-1α, recruiting endothelial progenitor cells/mesenchymal stem cells, as well as suppressing inflammation, generation of oxidative stress and cell apoptosis. Accordingly, this book chapter reviews the current data, that is, experimental studies and clinical trials focusing on the safety and efficacy as well as the underlying mechanisms of ESWT on improving ischemia-related organ dysfunction.
Published: 1 March 2018
Hellenic Journal of Cardiology, Volume 59, pp 78-90; doi:10.1016/j.hjc.2018.01.010

The development of stem-cell therapies for chronic ischemic heart failure is highly sought after to attempt to improve morbidity and mortality of this prevalent disease. This article reviews clinical trials investigating stem cell therapy for chronic ischemic heart failure. To generate this review article, PubMed was searched using keywords “stem cell therapy heart failure” with the article type “Clinical Trial” selected on 10/04/2016. The raw search yielded 156 articles. 53 articles were selected for inclusion in the review between the original literature search and manual research/cross-referencing. Additional reviews and original articles were also manually researched and cross-referenced. Cellular based therapies utilizing peripheral blood progenitor cells, bone marrow cells, mesenchymal stem cells, cells of cardiac origin, and embryonic stem cells have yielded mixed results, but some studies have shown modest efficacy. Skeletal myoblasts raised concerns about safety due to arrhythmias. Optimizing cell type and delivery method will be of critical importance in enhancing efficacy of therapy within various subsets of chronic ischemic heart failure patients. Although much more work needs to be done to optimize treatment strategies, developing stem cell therapies for chronic ischemic heart failure could be of critical importance to lessening the impactful burden that heart failure has on patients and society.
Thomas J. Povsic
Circulation Research, Volume 122, pp 552-554; doi:10.1161/circresaha.117.312520

> For the race is not always to the swift …. > > —Aesop (600–564 BC) After 25 years of research and well over a decade after the first randomized blinded clinical trials suggested benefit of stem cell therapy on cardiac performance, the field seems no closer to clinical approval of a product, and skepticism exists about the viability of the idea that myocardial regeneration can be effected. What has kept the field from crossing the finish line of clinical approval and is the goal in site? From a regulatory perspective, the efficacy and safety of regenerative approaches remain unproven.1 Despite significant expenditures of time and funding, definitive adequately powered trials have yet to be completed. Many of the challenges in the field of myocardial regeneration reflect obstacles in cardiovascular drug development as a whole. Improvements in the treatment of cardiovascular disease have resulted in dramatic reductions in cardiovascular mortality and have extended the life span of patients with cardiovascular disease but have also resulted in an increased prevalence of chronic conditions like congestive heart failure and refractory angina. These improvements in care have paradoxically increased the burden of disease and need for new therapies while exponentially increasing the number of patients required to demonstrate effectiveness. Recent estimates indicate that the cost of bringing a new drug to market increased from $140 million in the 1970s to >$2.5 billion in 2014 and tripled in the past decade alone.2 The implications of this can be seen in an example from the field of heart failure: although the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study; published in 1987) proved a mortality benefit of angiotensin-converting enzyme inhibition after following up 253 patients for 6 months, the benefit of sacubitril/valsartan in 2014 required enrollment of >8000 patients and 27-month follow-up to demonstrate an effect on …
, Gregor Zemljič, , Andraž Cerar, Vesna Andročec, Matjaž Sever, Peter Černelč
Published: 18 January 2018
Stem Cells International, Volume 2018, pp 1-8; doi:10.1155/2018/6487812

Aim of the Review. The aim of this review is to discuss recent advances in clinical aspects of stem cell therapy in chronic nonischemic heart failure (DCMP) with emphasis on patient selection, stem cell types, and delivery methods. Recent Findings. Several stem cell types have been considered for the treatment of DCMP patients. Bone marrow-derived cells and CD34+ cells have been demonstrated to improve myocardial performance, functional capacity, and neurohumoral activation. Furthermore, allogeneic mesenchymal stem cells were also shown to be effective in improving heart function in this patient population; this may represent an important step towards the development of a standardized stem cell product for widespread clinical use in patients with DCMP. Summary. The trials of stem cell therapy in DCMP patients have shown some promising results, thus making DCMP apparently more inviting target for stem cell therapy than chronic ischemic heart failure, where studies to date failed to demonstrate a consistent effect of stem cells on myocardial performance. Future stem cell strategies should aim for more personalized therapeutic approach by establishing the optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient’s age and stage of the disease.
Published: 1 January 2018
Pharmacological Research, Volume 127, pp 67-76; doi:10.1016/j.phrs.2017.06.001

Heart failure and acute myocardial infarction are conditions that are associated with high morbidity and mortality. Significant dysfunction of the heart muscle can occur as the consequence of end-stage chronic cardiovascular diseases or acute ischemic events that are marked by large infarction area and significant tissue necrosis. Despite the remarkable improvement of conventional treatments, a substantial proportion of patients still develops severe heart failure that can only be resolved by heart transplantation or mechanical device implantation. Therefore, novel approaches based on stem-cell therapy can directly modify the disease process and alter its prognosis. The ability of the stem-cells to modify and repair the injured myocardium is a challenging but intriguing concept that can potentially replace expensive and invasive methods of treatment that are associated with increased risks and significant financial costs. In that sense, granulocyte colony-stimulating factor (G-CSF) seems as an attractive treatment approach. Based on the series of pre-clinical experiments and a limited amount of clinical data, it was demonstrated that G-CSF agents possess the ability to mobilize stem-cells from bone marrow and induce their differentiation into cardiomyocytes or endothelial cells when brought into contact with injured regions of the myocardium. However, clinical benefits of G-CSF use in damaged myocardium remain unclear and are the topic of expert discussion. The main goal of this review is to present relevant and up-to-date evidence on G-CSF therapy use in pre-clinical models and in humans and to provide a rationale for its potential clinical applications in the future.
Encyclopedia of Cardiovascular Research and Medicine pp 469-483; doi:10.1016/b978-0-12-809657-4.65417-0

Stem cell administration has emerged as a novel therapy for the treatment of cardiovascular disease and has been successfully translated from bench to bedside. Numerous cell types have been evaluated in clinical trials to treat both acute and chronic cardiac disease, and some demonstrate the great capacity to repair the damaged heart. However, there remains great controversy regarding the ideal cell type, source, and method and timing of delivery, as not all clinical trials demonstrate efficacy. In this chapter, we discuss the current status of clinical trials and future perspectives of cell-based therapy for cardiac disease.
Melissa Vanover, ,
Published: 1 November 2017
Placenta, Volume 59, pp 107-112; doi:10.1016/j.placenta.2017.05.010

Placental stem cells are of growing interest for a variety of clinical applications due to their multipotency and ready availability from otherwise frequently discarded biomaterial. Stem cells derived from the placenta have been investigated in a number of disease processes, including wound healing, ischemic heart disease, autoimmune disorders, and chronic lung or liver injury. Fetal intervention for structural congenital defects, such as spina bifida, has rapidly progressed as a field due to advances in maternal-fetal medicine and improving surgical techniques. In utero treatment of structural, as well as non-structural, congenital disorders with cell-based therapies is of particular interest given the immunologic immaturity and immunotolerant environment of the developing fetus. A comprehensive literature review was performed to assess the potential utilization of placenta-derived stem cells for in utero treatment of congenital disorders. Most studies are still in the preclinical phase, utilizing animal models of common congenital disorders. Future research endeavors may include autologous transplantation, gene transfers, induced pluripotent stem cells, or cell-free therapies derived from the stem cell secretome. Though much work still needs to be done, placental stem cells are a promising therapeutic agent for fetal intervention for congenital disease.
Angela Castellanos Rieger, Bryon A Tompkins, Makoto Natsumeda, Victoria Florea, Kevin Collon, Jose Rodriguez, Marcus Rosado, Wayne Balkan, Joshua M Hare, Ivonne H Schulman
Circulation Research, Volume 121; doi:10.1161/res.121.suppl_1.8

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular morbidity and mortality. Left ventricular (LV) hypertrophy and heart failure with preserved ejection fraction (HFpEF) are the primary manifestations of the cardiorenal syndrome in 60 to 80% of CKD patients. Therapies that improve morbidity and mortality in HFpEF are lacking. Stem cell therapy reduces fibrosis, increases neovascularization, and promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model. Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: allogeneic (allo-) MSC (10х10 6 ), allo-kidney c-kit + cells (c-kit; 10х10 6 ), combination (MSC+c-kit; 1:1 ratio [5х10 6 each]), or placebo (each n=5). Cell therapy was delivered via the patent renal artery. Kidney function, renal and cardiac MRI, and PV loops were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization. Results: The CKD model was confirmed by increased creatinine and BUN and decreased GFR. Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks (p=0.7). HFpEF was demonstrated at 4 weeks by increased LV mass (20.3%; p= 0.0001), wall thickening (p<0.008), EDP (p=0.01), EDPVR (p=0.005), and arterial elastance (p=0.03), with no change in EF. Diffuse intramyocardial fibrosis was evident in histological analysis and delayed enhancement MRI imaging. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). GFR significantly improved in the combination group (p=0.033). EDV increased in the placebo (p=0.009) and c-kit (p=0.004) groups. ESV increased most in the placebo group (7.14±1.62ml; p=0.022). EF, wall thickness, and LV mass did not differ between groups at 12 weeks. Conclusion: A CKD large animal model manifests the characteristics of HFpEF. Intra-renal artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the combination and MSC groups. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.
Anastasija Rascanin, Ivana Arandjelovic, Mila Bastac, Dusan Bastac, , Aranđelović Ivana, Bastać Mila, Bastać Dušan
Timocki medicinski glasnik, Volume 42, pp 102-109; doi:10.5937/tmg1702102r

Cardiac insufficiency represents a syndrome caused by a wide spectrum of structural heart diseases, which makes the heart unable to provide enough blood supply to meet the body’s needs for oxygen. We can see the course of diagnostics and treatment of severe cardiac insufficiency in our patient who has previously been diagnosed with dilatational cardiomyopathy with mixed etiology (ischemic, diabetes, ethylism). There is a significant resistance to dispensation of peroral diuretics in chronic cardiac insufficiency and much better response to switching the type of oral diuretic: bumetanide instead of furosemide. The patient, who was, seemingly, in terminal phase of cardiac insufficiency with an idea to be treated by reconstruction of mitral valve, stem cells, cardioverter defibrillator and placement on a heart transplant list, has made a solid recovery using conventional cardiac insufficiency therapy The prognosis has been significantly improved, in spite of estimated high rate of mortality using the Seattle Heart Failure Model. A detailed analysis of two-dimensional and Doppler parameters routinely obtained from echocardiography provided significant prognostic information in this patient. The ejection fraction of this patient, with optimal non-pharmacological and pharmacological therapy, increased satisfactorily in 3.5 years by 14% (EF 18% versus 32%), although without regression of left ventricle dilatation, but with size reduction of left atrium and improvement of diastolic dysfunction .The therapy was based on the recommendation of the European Guide for Cardiac Insufficiency published in 2016: ACE inhibitor, beta-blocker, spironolactone, bumetanide, acetylsalicylic acid, statin, with good regulation of diabetes and mild physical activity. Although prospective clinical studies are still to be conducted, the use of echocardiography in an individual case to monitor treatment success and risk segregation should be included in a modern strategy for the treatment of cardiac insufficiency and have an impact on clinical decision for heart transplantation.
Stem Cells in Clinical Applications; doi:10.1007/978-3-319-46693-4

This invaluable resource discusses clinical applications with effects and side-effects of applications of stem cells in liver, lung and heart regeneration. All chapters are contributed by pre-eminent scientists in the field and covers such topics as cell therapy in the treatment of cirrhosis and other liver, heart and lung diseases, characteristics of hepatic progenitor cells, future directions of the discussed therapies and much more. Liver, Lung and Heart Regeneration and the other books in the Stem Cells in Clinical Applications series will be invaluable to scientists, researchers, advanced students and clinicians working in stem cells, regenerative medicine or tissue engineering.
Josue Chery, Joshua Wong, Shan Huang, Shuyun Wang, Ming-Sing Si, Miss Shan Huang
Tissue Engineering Part B: Reviews, Volume 22, pp 459-469; doi:10.1089/ten.teb.2016.0136

Hypoplastic left heart syndrome (HLHS), the most severe and common form of single ventricle congenital heart lesions, is characterized by hypoplasia of the mitral valve, left ventricle (LV) and all LV outflow structures. While advances in surgical technique and medical management have allowed survival into adulthood, HLHS patients have severe morbidities, decreased quality of life and a shortened lifespan. The single right ventricle (RV) is especially prone to early failure because of its vulnerability to chronic pressure-overload, a mode of failure distinct from ischemic cardiomyopathy encountered in acquired heart disease. As these patients enter early adulthood, an emerging epidemic of RV failure has become evident. Regenerative medicine strategies may help preserve or boost RV function in children and adults with HLHS by promoting angiogenesis and mitigating oxidative stress. Rescuing a RV in decompensated failure may also require the creation of new, functional myocardium. Although considerable hurdles remain before their clinical translation, stem cell therapy and cardiac tissue engineering possess revolutionary potential in the treatment of pediatric and adult patients with HLHS who currently have very limited long-term treatment options.
Scandinavian Cardiovascular Journal, Volume 50, pp 293-299; doi:10.1080/14017431.2016.1210213

Although, treatment of ischemic heart disease (IHD) has improved considerably within the last decades, it is still the main cause of death worldwide. Despite maximum treatment, many IHD patients suffer from refractory angina and heart failure, which severely limits their daily lives. Moreover, IHD is very costly for the health care system. Therefore, new treatment options and strategies are being researched intensely. Stem cell therapy to improve myocardial perfusion and stimulate growth of new cardiomyocytes could be a new way to go. Nevertheless, the results from clinical studies have varied considerably, probably due to the use of many different cell lines obtained from different tissues and the different patient populations. The present review will focus on treatment with the mesenchymal stromal cell from bone marrow and adipose tissue in animal and patients with acute and chronic IHD (CIHD).
Chuan-Bin Liu, He Huang, Ping Sun, Shi-Ze Ma, An-Heng Liu, Jian Xue, Jin-Hui Fu, Yu-Qian Liang, Bing Liu, Dong-Ying Wu, et al.
STEM CELLS Translational Medicine, Volume 5, pp 1004-1013; doi:10.5966/sctm.2015-0298

Stem cell therapy has emerged as a new strategy for treatment of ischemic heart disease. Although umbilical cord‐derived mesenchymal stromal cells (UC‐MSCs) have been used preferentially in the acute ischemia model, data for the chronic ischemia model are lacking. In this study, we investigated the effect of UC‐MSCs originated from Wharton's jelly in the treatment of chronic myocardial ischemia in a porcine model induced by ameroid constrictor. Four weeks after ameroid constrictor placement, the surviving animals were divided randomly into two groups to undergo saline injection (n = 6) or UC‐MSC transplantation (n = 6) through the left main coronary artery. Two additional intravenous administrations of UC‐MSCs were performed in the following 2 weeks to enhance therapeutic effect. Cardiac function and perfusion were examined just before and at 4 weeks after intracoronary transplantation. The results showed that pigs with UC‐MSC transplantation exhibited significantly greater left ventricular ejection fraction compared with control animals (61.3% ± 1.3% vs. 50.3% ± 2.0%, p < .05). The systolic thickening fraction in the infarcted left ventricular wall was also improved (41.2% ± 3.3% vs. 46.2% ± 2.3%, p < .01). Additionally, the administration of UC‐MSCs promoted collateral development and myocardial perfusion. The indices of fibrosis and apoptosis were also significantly reduced. Immunofluorescence staining showed clusters of CM‐DiI‐labeled cells in the border zone, some of which expressed von Willebrand factor. These results suggest that UC‐MSC treatment improves left ventricular function, perfusion, and remodeling in a porcine model with chronic myocardial ischemia. Significance Ischemic heart disease is the leading cause of death worldwide. Many patients with chronic myocardial ischemia are not suitable for surgery and have no effective drug treatment; they are called “no‐option” patients. This study finds that umbilical cord‐derived mesenchymal stromal cells transplanted by intracoronary delivery combined with two intravenous administrations was safe and could significantly improve left ventricular function, perfusion, and remodeling in a large‐animal model of chronic myocardial ischemia, which provides a new choice for the no‐option patients. In addition, this study used clinical‐grade mesenchymal stem cells with delivery and assessment methods commonly used clinically to facilitate further clinical transformation.
, , Charles R. Lambert, Jay H. Traverse, Richard Schatz, Marco Costa, Thomas J. Povsic, , James T. Willerson, Steven Kesten, et al.
Catheterization and Cardiovascular Interventions, Volume 89, pp 169-177; doi:10.1002/ccd.26601

Objective To assess safety and feasibility of autologous adipose‐derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. Background Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. Methods The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double‐blind trials assessing intramyocardial (IM) ADRC delivery [40‐million, n = 28 (ATHENA) and 80‐million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II–IV) or heart failure (NYHA Class II–III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on‐site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. Results Enrollment was terminated prematurely due to non‐ADRC‐related adverse events and subsequent prolonged enrollment time. Thirty‐one patients (17‐ADRCs, 14‐placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. −9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12‐months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12‐months with significant improvement in MLHFQ (−21.6 + 13.9 vs. −5.5 + 23.8, P = 0.038). Conclusions A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in “no option” CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs.
, Naja D Mygind, Abbas A Qayyum,
Published: 19 February 2016
Minerva Cardioangiol, Volume 64

The publisher has not yet granted permission to display this abstract.
Roshni Khatiwala,
Published: 16 January 2016
Stem Cell Reviews and Reports, Volume 12, pp 214-223; doi:10.1007/s12015-016-9642-z

Myocardial infarctions and chronic ischemic heart disease both commonly and disproportionately affect elderly patients more than any other patient population. Despite available treatments, heart tissue is often permanently damaged as a result of cardiac injury. This review aims to summarize recent literature proposing the use of modified autologous adult stem cells to promote healing of post-infarct cardiac tissue. This novel cellular treatment involves isolation of adult stem cells from the patient, in vitro manipulation of these stem cells, and subsequent transplantation back into the patient's own heart to accelerate healing. One of the hindrances affecting this process is that cardiac issues are increasingly common in elderly patients, and stem cells recovered from their tissues tend to be pre-senescent or already in senescence. As a result, harsh in vitro manipulations can cause the aged stem cells to undergo massive in vivo apoptosis after transplantation. The consensus in literature is that inhibition or reversal of senescence onset in adult stem cells would be of utmost benefit. In fact, it is believed that this strategy may lower stem cell mortality and coerce aged stem cells into adopting more resilient phenotypes similar to that of their younger counterparts. This review will discuss a selection of the most efficient and most-recent strategies used experimentally to enhance the effectiveness of current stem cell therapies for ischemic heart diseases.
The Indian Journal of Nutrition and Dietetics, Volume 53; doi:10.21048/ijnd.2016.53.1.3882

New research reveals combined cell therapy enhances cardiac performance following heart attack. A study by Dr. Joshua Hare, Director of Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami Miller School of Medicine finds that combination stem cell therapy, using ckit+ cardiac stem cells (CSCs) and mesenchymal stem cells (MSCs) can significantly enhance cardiac performance in chronic ischemic cardiomyopathy following a heart attack. The study centered on large animals three months after experiencing a heart attack. The animals were divided into three cohorts. The first group received transendocardial injections of MSCs, while the second group received a combination of MSCs and cardiacderived CSCs. The third group acted as a controlled placebo group. Cardiac MRIs were performed to determine cardiac function before and after therapy. Both groups of cell-treated animals exhibited a significant reduction in scar size. However, the group that received the combination of MSCs and cardiacderived CSCs also demonstrated increased viable tissue, improved contractile performance and increased formation of new cardiomyocytes, which contribute to heart repair. The group that received the combination cell therapy continued to show substantial cardiac enhancement for at least three months post treatment. While further testing is needed, these findings establish the safety and efficacy of combination cell-based treatments, taking the next steps in developing stem cell-based therapies for the prevention and treatment of cardiovascular disease in humans.
Motoko Shiozaki, Shigeru Miyagawa, Satsuki Fukushima, Itsunari Minami, Keitaro Domae, Shin Yajima, Emiko Ito, Kazuhiro Aiba, Takashi Asada, Norio Nakatsuji, et al.
Circulation, Volume 132; doi:10.1161/circ.132.suppl_3.13789

Background: Use of induced pluripotent stem cells (hiPSC) is promising to establish cardiac regenerative medicine in clinical arena; however, safety is concerned by regulatory scientific view, including use of xeno-biological materials for production of the graft. We have explored synthetic small molecules, KY, instead of standard xeno-materials to induce cardiomyogenic differentiation, such as BMP4, Activin A or insulin. We herein studied therapeutic efficacy of hiPSC-derived cardiomyocytes (CMs) generated by xeno-free condition on chronic myocardial infarction (MI) in rat. Methods: Lentivirus vector carrying Oct3/4, Sox2 and Klf4 was transfected in human dermal fibroblasts to establish hiPSC cell-line. KY was added to the hiPSCs, which displayed 80±10%-positivity in cardiac-troponin T. Scaffold-free cardiac graft was produced by hiPSC-CMs that were cultured in thermoresponsive dishes, and transplanted over the cardiac surface of athymic nude rats that were subjected to left coronary artery ligation 2 weeks prior to the treatment, or sham operation was performed. Results: Echocardiographically, ejection fraction recovered after the treatment in the hiPSC-CM group (48±4% at baseline, 55±4% at 1 week, 55±4% at 2 weeks, and 56±3% at 4 weeks), whereas the sham group showed gradual reduction in ejection fraction (46±5% at baseline, 42±5% at 1 week, 38±4% at 2 weeks, and 34±6% at 4 weeks). Immunohistochemistry showed that cardiac-troponin T and human nuclear antigen double positive-hiPSC-CMs were present in the lateral cardiac surface in the hiPSC-CM hearts. In the hiPSC-CM group, collagen fibers significantly decreased in the infarct-border and remote areas (p<0.01 and p<0.01, respectively). CD31-positve capillary number in the infarct-border area was significantly greater in the hiPSC-CM group (p<0.01) than the sham group. Conclusion: Transplantation of scaffold-free human iPSC-CMs grafts produced by xeno-free synthetic small molecules was effective on rat chronic MI heart, warranting further studies to optimize production of iPSC-based artificial cardiac graft for cardiac regeneration therapy.
Current Opinion in Cardiology, Volume 30, pp 301-310; doi:10.1097/hco.0000000000000167

The aim of this review was to discuss recent advances in clinical aspects of stem cell therapy in heart failure with emphasis on patient selection, stem cell types and delivery methods.Several stem cell types have been considered for the treatment of patients with heart failure. In nonischemic heart failure, transplantation of CD34 cells improved myocardial performance, functional capacity and neurohumoral activation. In ischemic heart failure, cardiosphere-derived cells were shown to reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. Both autologous and allogeneic mesenchymal stem cells were shown to be effective in improving heart function in patients with ischemic heart failure; this may represent an important step toward the development of a standardized stem cell product for widespread clinical use.Although trials of stem cell therapy in heart failure have shown promising results, the findings are not consistent. Given the wide spectrum of heart failure, it may be difficult to define a uniform stem cell therapy for all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and disease state.
Dominique Shum-Tim, Khalid Ridwan, Mohammad Alrefai, John Connell, Arghya Paul, Divya Murali
Stem Cells and Cloning: Advances and Applications, pp 81-101; doi:10.2147/sccaa.s54204

Cardiac tissue engineering and regeneration using cell-based therapy Mohammad T Alrefai,1–3 Divya Murali,4 Arghya Paul,4 Khalid M Ridwan,1,2 John M Connell,1,2 Dominique Shum-Tim1,2 1Division of Cardiac Surgery, 2Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada; 3King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; 4Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells. Keywords: stem cells, cardiomyocytes, cardiac surgery, heart failure, myocardial ischemia, heart, scaffolds, organoids, cell sheet and tissue engineering
Published: 17 March 2015
Journal of Nuclear Cardiology, Volume 22, pp 666-672; doi:10.1007/s12350-015-0078-7

Heart failure is a devastating disease with high morbidity and mortality. In 2013, approximately 5.1 million people suffered from chronic heart failure in the United States.1 About 50% of these individuals died within 5 years of their initial diagnosis.1 The most common cause of heart failure is coronary artery disease. Unfortunately, treatment options remain limited. Current medical therapy, including angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, and angiotensin and adrenergic receptor blockers, only slow disease progression. The chronic shortage of donor organs restricts the number of heart transplantations performed. Although novel approaches to cardiac regeneration, such as stem cell and gene therapy, are under investigation, proving efficacy and safety requires extensive preclinical studies before “first in man” studies can be performed. The success of clinical translation is highly dependent on how well animal models can recapitulate disease in humans a ...
, , Samer Mansour, Uswa Shahzad, , Terrence M. Yau
Published: 1 November 2014
Canadian Journal of Cardiology, Volume 30, pp 1361-1369; doi:10.1016/j.cjca.2014.04.031

After ischemic injury, the endogenous repair mechanisms of the human heart are insufficient for meaningful tissue regeneration, so muscle lost is replaced by noncontractile scar tissue. Current treatments for ischemic cardiomyopathy improve quality of life and increase life expectancy, but cannot cure the underlying disease of cardiomyocyte loss. Cellular transplantation is emerging as a valuable therapeutic approach to heal the ischemic heart. Adult bone marrow stem cells are capable of differentiation, regeneration of infarcted myocardium, and induction of myogenesis and angiogenesis, ultimately leading to improved contractility. Positive results from animal studies have prompted several clinical trials to ascertain the safety and feasibility of cell therapy. However, despite all the excitement in stem cell research resulting from initial experimental data and preliminary clinical trials, the mixed results observed have raised many unanswered questions. A major obstacle to the identification of the optimal cell therapy is that the fate of the implanted cells and the nature of their beneficial effects are ill-defined. A better understanding is fundamental for the development of new therapeutic agents, and to optimize stem cell applications. Well-designed and powered double-blinded randomized studies are clearly needed to confirm promising findings from early studies. With several ongoing randomized trials directed toward evaluation of stem cell therapies in patients with acute or chronic ischemic cardiomyopathy, the Canadian initiative represents a milestone.
, , , Giuseppe Gaipa, , Felice Achilli, Paolo Scacciatella, ,
Stem Cells and Development, Volume 23, pp 2403-2421; doi:10.1089/scd.2014.0111

Ischemic diseases are the major cause of death and morbidity in Western countries. In the last decade, cell therapy has been suggested to be a promising treatment both in acute/chronic myocardial and peripheral ischemia. Different cell lineages have been tested, including endothelial progenitor cells. A subpopulation of bone marrow-derived immature ECPs, expressing the highly conserved stem cell glycoprotein antigen prominin-1 or CD133 marker, was shown to possess pro-angiogenic and antiapoptotic effects on ischemic tissues. The mechanisms implicated in CD133+ cells ability to contribute to neovascularization processes have been attributed to their ability to directly differentiate into newly forming vessels and to indirectly activate pro-angiogenic signaling by paracrine mechanisms. A large body of in vivo experimental evidences has demonstrated the potential of CD133+ cells to reverse ischemia. Moreover, several clinical trials have reported promising beneficial effects after infusion of autologous CD133+ into ischemic heart and limbs exploiting various delivery strategies. These trials have contributed to characterize the CD133+ manufacturing process as an advanced cell product (AMP). The aim of this review is to summarize available experimental and clinical data on CD133+ cells in the context of myocardial and peripheral ischemia, and to focus on the development of the CD133+ cell as an anti-ischemic AMP.
Christopher Blomberg, Juyong Lee,
Current Pharmaceutical Design, Volume 20, pp 4906-4910; doi:10.2174/1381612819666131125153030

Myocardial infarction, heart failure, and chronic ischemic heart disease account for the majority of the cardiovascular burden. The current treatment strategies focus on limiting the progression of disease and preserving cardiac myocardium. The goal of stem cell therapy, on the other hand, is to reverse or replace damaged cardiac tissue. Over the past two decades many studies have been conducted to understand stem cell performance, survival, and the potential for cardiac repair. Neuregulin1, an epidermal growth factor family member, promotes embryonic stem cell differentiation into the cardiac lineage and improves survival in bone marrow-derived mesenchymal stem cell and embryonic endothelial progenitor cells. Current clinical trials are actively pursuing Neuregulin1's therapeutic potential in the areas of heart failure and cardiac ischemia. It is the intent of this paper to review the current knowledge of Neuregulin1 in stem cell biology and discuss the potential of using Neuregulin1 to improve stem cell therapy for cardiac repair.
Brian R Weil, Amanda Ribbeck, Gen Suzuki, Merced M Leiker, James A Fallavollita, John M Canty
Circulation Research, Volume 115; doi:10.1161/res.115.suppl_1.21

Objective: icCDCs improve function of ischemic myocardium and increase cardiomyocyte nuclear density but the extent to which this is explained by an increase in nuclei per cell vs. the formation of new myocytes is unclear. We aimed to address this issue and quantify new myocyte formation throughout the left ventricle (LV) after global icCDC treatment in swine with hibernating myocardium. Methods: Swine with a chronic LAD stenosis (N=29) received either ~35 x 10 6 icCDCs or no treatment. Regional function (echocardiography) and myocyte morphometric indices were assessed 1 month later. Transverse and longitudinal tissue sections were used to measure regional myocyte nuclear density, diameter, length, and nuclei/cell, from which myocyte volume and myocytes per gram of myocardium were calculated. Results: icCDC-mediated improvements in regional function were accompanied by an increase in myocyte nuclear density without a change in the number of nuclei/cell (Table). Compared with untreated animals, icCDC-treated animals exhibited a reduction in myocyte volume and a reciprocal increase in the number of myocytes per gram of tissue. Anatomic LV hypertrophy did not occur, however, as LV mass/body mass ratio was not different between groups (untreated: 2.5 ± 0.1 vs. icCDCs: 2.3 ± 0.1). Conclusion: These data demonstrate that icCDCs produce significant myocyte regeneration throughout the regionally ischemic heart that is dissociated from alterations in LV mass. Changes in myocyte nuclear density do not reflect an altered number of nuclei/cell and quantitative estimates suggest that intracoronary delivery of CDCs to the entire LV increases the number of myocytes by ~25% in just 4 weeks.
Current Treatment Options in Cardiovascular Medicine, Volume 16, pp 1-19; doi:10.1007/s11936-014-0324-3

The discovery of adult cardiac stem cells (CSCs) and their potential to restore functional cardiac tissue has fueled unprecedented interest in recent years. Indeed, stem-cell–based therapies have the potential to transform the treatment and prognosis of heart failure, for they have the potential to eliminate the underlying cause of the disease by reconstituting the damaged heart with functional cardiac cells. Over the last decade, several independent laboratories have demonstrated the utility of c-kit+/Lin- resident CSCs in alleviating left ventricular dysfunction and remodeling in animal models of acute and chronic myocardial infarction. Recently, the first clinical trial of autologous CSCs for treatment of heart failure resulting from ischemic heart disease (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) has been conducted, and the interim results are quite promising. In this phase I trial, no adverse effects attributable to the CSC treatment have been noted, and CSC-treated patients showed a significant improvement in ejection fraction at 1 year (+13.7 absolute units versus baseline), accompanied by a 30.2 % reduction in infarct size. Moreover, the CSC-induced enhancement in cardiac structure and function was associated with a significant improvement in the New York Heart Association (NYHA) functional class and in the quality of life, as measured by the Minnesota Living with Heart failure Questionnaire. These results are exciting and warrant larger, phase II studies. However, CSC therapy for cardiac repair is still in its infancy, and many hurdles need to be overcome to further enhance the therapeutic efficacy of CSCs.
, Annette Ekblond, Mandana Haack-Sørensen, Anders B. Mathiasen, Abbas A. Qayyum
Adult and Pluripotent Stem Cells pp 143-167; doi:10.1007/978-94-017-8657-7_8

The clinical consequence of the increasing incidence of coronary artery disease is a growing problem worldwide and ischemic heart disease remains the most common cause of death and a major cause of hospital admissions in industrialised countries. Early treatment with stabilizing drugs and mechanical revascularization by percutaneous coronary intervention or coronary by-pass surgery has reduced the mortality significantly. However, there is still a group of patients, which cannot be treated satisfactorily with these interventions. Treatment with genes encoding vascular growth factors or stem cells with the potential to regenerate the damaged myocardium is a relatively new approach. The results from early clinical studies on gene and stem cell therapy for cardiac regeneration in patients with acute or chronic ischemic heart disease have been inconsistent. Some of the discrepancy could be due to differences in study designs or patient selection. This review will present the conducted clinical trials and try to clarify the influence of patient selection, chosen cell type, cell source, delivery methods and mechanisms of action on the differences in results.
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