Stem Cells and Development
ISSN / EISSN: 15473287 / 15578534
Published by: Mary Ann Liebert Inc
Total articles ≅ 3,119
Latest articles in this journal
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0253
Stem cell niches have been thoroughly investigated in tissue with high regenerative capacity but not in tissues where cell turnover is slow, such as the human heart. The left AtrioVentricular junction (AVj), the base of the mitral valve, has previously been proposed as a niche region for cardiac progenitors in the adult human heart. In the present study, we explore the right side of the human heart; the base of the tricuspid valve, to investigate the potential of this region as a progenitor niche. Paired biopsies from explanted human hearts were collected from multi organ donors (N=12). The lateral side of the AVj, right atria (RA) and right ventricle (RV) were compared for the expression of stem cell niche-related biomarkers using RNA sequencing. Gene expression data indicated upregulation of genes related to embryonic development and extracellular matrix composition in the proposed niche region, i.e. the AVj. In addition, immunohistochemistry showed high expression of the fetal cardiac markers MDR1, SSEA4, and WT1 within the same region. Nuclear expression of HIF1-α was detected suggesting hypoxia. Rare cells were found with the co-staining of the proliferation marker PCNA and Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac TroponinT (cTnT), indicating proliferation of small cardiomyocytes. WT1+/cTnT+ and SSEA4+/cTnT+ cells were also found, suggesting cardiomyocyte specific progenitors. The expression of the stem cell markers gradually decreased with distance from the tricuspid valve. No expression of these markers was observed in the RV tissue. In summary, the base of the tricuspid valve is an extracellular matrix rich region containing cells with expression of several stem cell niche-associated markers. Co-expression of stem cell markers with cTnT indicates cardiomyocyte specific progenitors. We previously reported similar data from the base of the mitral valve and thus propose that human adult cardiomyocyte progenitors reside around both atrioventricular valves.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0238
Mesenchymal stromal/stem cells (MSCs) are a promising therapeutic agent for various diseases, including sepsis. However, translating MSC therapy to clinical applications remains challenging due to variations in the properties of MSCs under different preparation conditions. In this study, the gene expression profiles of human adipose-derived mesenchymal stromal/stem cells (ADSCs) under different culture conditions were compared in relation to their therapeutic efficacy for sepsis. Results showed that ADSCs cultured in media supplemented with human platelet lysates (hPL-ADSCs) exhibited a smaller cell size and higher proliferative capacity, while ADSCs cultured in media supplemented with fetal bovine serum (FBS-ADSCs) showed a broader and flatter shape. Both hPL-ADSCs and FBS-ADSCs exhibited a protective effect in a mouse model of sepsis; however, hPL-ADSCs displayed a better potency for immunosuppressive function, as evidenced by a better improvement of survival rate and further reduction of tissue injury and infectious biomarkers (ALT and PCT). Furthermore, hPL-ADSCs caused a more anti-inflammatory transcriptomic shift, while FBS-ADSCs led to more depression of pro-inflammatory transcriptomic response. This study thus demonstrates that both hPL-ADSCs and FBS-ADSCs are effective for anti-septic therapy via different mechanisms of inflammatory manipulation, although hPL-ADSCs may imply a better preference.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0180
Adult-derived mesenchymal stem cells (MSCs) can be used in therapies for the treatment of various diseases. MSCs derived from aging tissues or long-term MSC cultures could have diminished therapeutic effects compared with MSCs derived from younger tissues, but the underlying mechanism has not been completely established. Dysfunction of energy metabolism is one of the main mechanisms underlying cell senescence. Although cyclic adenosine monophosphate (cAMP) is known to inhibit cell division and proliferation in vitro, its impact on MSC senescence has not been described. In this study, we used forskolin, an adenylate cyclase agonist and cAMP inducer, to disrupt metabolism in human adipose-derived MSCs and investigate the effects of metabolic dysfunction on MSC senescence. Treatment of human MSCs with forskolin resulted in senescence phenotypes, including reduced proliferation, cell-cycle arrest, and enhanced expression of the cell aging markers p16 and p21. Furthermore, the senescent MSCs exhibited increased adipogenesis capacity and decreased osteogenesis capacity as well as a senescence-associated secretory phenotype characterized by increased expression of several inflammatory factors. Forskolin-associated MSC senescence was mainly caused by oxidative stress–induced disruption of mitochondrial metabolism, and the senescent MSCs had high levels of reactive oxygen species and reduced sirtuin gene expression. Lastly, we found that cAMP inhibitor SQ22536 protects MSCs from forskolin-induced senescence and senescence-related-inflammatory-phenotype (SASP). Our results indicate that forskolin can cause senescence of human MSCs through oxidative stress–induced mitochondrial metabolic dysfunction, and thus the results provide a basis for developing strategies for improving the quality and efficacy of cultured MSCs for clinical use.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0244
Peritoneal fibrosis is a critical sequela that limits the application of peritoneal dialysis (PD). This study explored the role and mechanism of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in preventing PD-associated peritoneal injury. C57BL/6 mice were randomized into three groups: a control (saline), peritoneal injury (2.5% glucose peritoneal dialysate + lipopolysaccharide (LPS)), and peritoneal injury + exosome group. After six weeks, mice were dissected, and the parietal peritoneum was collected. The level of peritoneal structural and functional damage was assessed. Additionally, transcriptome analysis of the peritoneum and miRNA sequencing on BMSC-Exos were performed. The parietal peritoneum had significantly thickened, and peritoneal function was impaired in the peritoneal injury group. Peritoneal structural and functional damage was significantly reduced after exosome treatment, while peritoneal inflammation, fibrosis, angiogenesis, and mesothelial damage significantly increased. Transcriptomic analysis showed that the BMSC-Exos affected the cell cycle process, cell differentiation, and inflammatory response regulation. Significant pathways in the exosome group were enriched by inflammation, immune response, and cell differentiation, which constitute a molecular network that regulates the peritoneal protective mechanism. Additionally, inflammatory factors (TNF-α, IL-1β), fibrosis markers (α-SMA, collagen-III, fibronectin), profibrotic cytokines (TGF-β1), and angiogenesis-related factor (VEGF) were downregulated at the mRNA and protein levels through BMSC-Exos treatment. BMSC-Exos treatment can prevent peritoneal injury by inhibiting peritoneal fibrosis, inflammation, and angiogenesis, showing a multi-target regulatory effect. Therefore, BMSC-Exos therapy might be a new therapeutic strategy for treating peritoneal injury.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0201
Mesenchymal stem cells (MSCs) are well known for their regenerative potential. Despite the fact that the ability of MSCs to proliferate and differentiate has been studied extensively, there still remains much to learn about the signalling mechanisms and pathways which control proliferation and influence differentiation phenotype. In recent years, there has been growing evidence for the utility of non-neuronal cholinergic signalling systems and that acetylcholine (ACh) plays an important, ubiquitous, role in cell-to-cell communication. Indeed, cholinergic signalling is hypothesised to occur in stem cells and ACh synthesis, as well as ACh receptor (AChR) expression, has been identified in several stem cell populations; including MSCs. Furthermore, AChRs have been found to influence MSC regenerative potential. In humans, there are two major classes of AChRs, muscarinic AChRs and nicotinic AChRs, with each class possessing several subtypes or subunits. In this review, the expression and function of AChRs in different types of MSC will be summarised with the aim of highlighting how AChRs play a pivotal role in regulating MSC regenerative function.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0257
Adipose-derived stem cells (ASCs), as a cell therapy with considerable therapeutic potential, have received increasing attention in tissue repair, endocrine regulation, immune regulation, and aging and obesity research. Gut microbiota are present in all organisms and play important roles in the development of aging and obesity. Dysbiosis activates inflammatory pathways that may contribute to the development of aging and obesity. We used C57BL/6J mice of different ages to carry out the experiment. Young mice were used as donors for ASC. Feces from the three groups were collected for 16sRNA sequencing to analyze the species composition of intestinal microorganisms. Then, predicted metabolic pathways by PICRUSt2 using 16s rRNA gene sequences. Immune cell levels in abdominal adipose tissue was assessed by flow cytometry. The content of IL-6、TNF-α and LPS in serum was measured by ELISA kit. Our 16sRNA sequencing data showed restoration of gut microbiota diversity and an increase in beneficial flora (Akkermansia, Lactobacillus, Prevotella) 7 days after ASC transplantation. In addition, the inflammatory environment improved in older transplanted mice.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0216
Cartilage is derived from the chondrogenic differentiation of stem cells, for which the regulatory mechanism has not been fully elucidated. N6-methyladenosine (m6A) mRNA methylation is the most common posttranscriptional modification in eukaryotic mRNAs and is mediated by m6A regulators. However, whether m6A regulators play roles in chondrogenic differentiation is unknown. Herein, we aim to determine the role of a main m6A reader protein, YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), in chondrogenic differentiation regulation. Western blotting assays found the expression of YTHDF1 increased during chondrogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The results of qPCR, western blotting, immunohistochemistry and Alcian blue staining revealed that overexpression of YTHDF1 increased cartilage matrix synthesis and the expression of chondrogenic markers when hBMSCs, ATDC5 cells, or C3H10T1/2 cells were induced to undergo chondrogenesis. Conversely, chondrogenesis was clearly inhibited when YTHDF1 was knocked down in hBMSCs, ATDC5 cells, or C3H10T1/2 cells. Further RNA sequencing and molecular biology experiments found that YTHDF1 activated the Wnt/β-catenin signaling pathway during chondrogenic differentiation. Finally, the effects of overexpression and knockdown of YTHDF1 on chondrogenic differentiation were reversed by inhibiting or activating β-catenin activity. Therefore, we demonstrated that YTDHF1 promoted chondrogenic differentiation through activation of the Wnt/β-catenin signaling pathway.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0226
Adverse intrauterine environments can cause persistent changes in epigenetic profiles of stem cells, increasing susceptibility of the offspring to developing metabolic diseases later in life. Effective approaches to restore the epigenetic landscape and function of stem cells remain to be determined. Here we investigated the effects of pharmaceutical activation of AMPK, an essential regulator of energy metabolism, on mitochondrial programming of Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) from women with diabetes during pregnancy. Induction of myogenic differentiation of WJ-MSCs was associated with increased PGC-1α expression and mitochondrial DNA abundance. Inhibition of DNA methylation by 5 Azacytidine significantly increased PGC-1α expression and mitochondrial DNA abundance in WJ-MSCs, which were abolished by AMPK inhibitor Compound C (CC), suggesting an AMPK-dependent role of DNA demethylation in regulating mitochondrial biogenesis in WJ-MSCs. Further, activation of AMPK in diabetic WJ-MSCs by AICAR or metformin decreased the level of PGC-1α promoter methylation and increased PGC-1α expression. Notably, decreased PGC-1α promoter methylation by transient treatment of AMPK activators persisted following myogenic differentiation. This was associated with enhanced myogenic differentiation capacity of human WJ-MSCs and increased mitochondrial function. Taken together, our findings revealed an important role for AMPK activators in epigenetic regulation of mitochondrial biogenesis and myogenesis in WJ-MSCs, which could lead to potential therapeutics for preventing fetal mitochondrial programming and long-term adverse outcome in offspring of women with diabetes during pregnancy.
Stem Cells and Development; https://doi.org/10.1089/scd.2022.0284
Many adult somatic stem cell lineages are comprised of subpopulations that differ in gene expression, mitotic activity, and differentiation status. Here we explored if cellular heterogeneity also exists within oogonial stem cells (OSCs), and how chronological aging impacts OSCs. In OSCs isolated from mouse ovaries by flow cytometry and established in culture, we identified subpopulations of OSCs that could be separated based on differential expression of stage-specific embryonic antigen 1 (SSEA1) and cluster of differentiation 61 (CD61). Levels of aldehyde dehydrogenase (ALDH) activity were inversely related to OSC differentiation, whereas commitment of OSCs to differentiation via transcriptional activation of stimulated by retinoic acid gene 8 was marked by a decline in ALDH activity and in SSEA1 expression. Analysis of OSCs freshly isolated from ovaries of mice between 3–20 months of age revealed that these subpopulations were present and persisted throughout adult life. However, expression of developmental pluripotency associated 3 (Dppa3), an epigenetic modifier which promotes OSC differentiation into oocytes, was lost as the mice transitioned from a time of reproductive compromise (10 months) to reproductive failure (15 months). Further analysis showed that OSCs from aged females could be established in culture, and that once established the cultured cells reactivated Dppa3 expression and the capacity for oogenesis. Analysis of single-nucleus RNA sequence datasets generated from ovaries of women in their 20s versus those in their late 40s to early 50s showed that the frequency of DPPA3-expressing cells decreased with advancing age, and this was paralleled by reduced expression of several key meiotic differentiation genes. These data support the existence of OSC subpopulations that differ in gene expression profiles and differentiation status. Additionally, an age-related decrease in Dppa3/DPPA3 expression, which is conserved between mice and humans, may play a role in loss of the ability of OSCs to maintain oogenesis with age.