Stem Cell Research & Therapy

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ISSN / EISSN : 1757-6512 / 1757-6512
Current Publisher: Springer Science and Business Media LLC (10.1186)
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Kai Nan, Yuankai Zhang, Xin Zhang, Dong Li, Yan Zhao, Zhaopu Jing, Kang Liu, Donglong Shang, Zilong Geng,
Stem Cell Research & Therapy, Volume 12, pp 1-13; doi:10.1186/s13287-021-02390-x

Abstract:
Background Local ischemia and defective osteogenesis are implicated in the progression of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies have revealed that exosomes released from adipose-derived stem cells (ASCs) play important roles in ONFH therapy. The present study aimed to investigate whether exosomes derived from miR-378-overexpressing ASCs (miR-378-ASCs-Exos) could promote angiogenesis and osteogenesis in GC-induced ONFH. Methods In vitro, we investigated the osteogenic potential of miR-378-ASCs-Exos on bone marrow stromal cells (BMSCs) by alkaline phosphatase staining and western blotting. The angiogenic effects of miR-378-ASCs-Exos on human umbilical vein endothelial cells (HUVECs) were examined by evaluating their proliferation, migration, and tube-forming analyses. We identified the underlying mechanisms of miR-378 in osteogenic and angiogenic regulation. In addition, an ONFH rat model was established to explore the effects of miR-378-ASCs-Exos through histological and immunohistochemical staining and micro-CT in vivo. Results Administration of miR-378-ASCs-Exos improved the osteogenic and angiogenic potentials of BMSCs and HUVECs. miR-378 negatively regulated the suppressor of fused (Sufu) and activated Sonic Hedgehog (Shh) signaling pathway, and recombinant Sufu protein reduced the effects triggered by miR-378-ASCs-Exos. In vivo experiments indicated that miR-378-ASCs-Exos markedly accelerated bone regeneration and angiogenesis, which inhibited the progression of ONFH. Conclusion Our study indicated that miR-378-ASCs-Exos enhances osteogenesis and angiogenesis by targeting Sufu to upregulate the Shh signaling pathway, thereby attenuating GC-induced ONFH development.
Ti-Dong Shan, Han Yue, Xue-Guo Sun, Yue-Ping Jiang, Li Chen
Stem Cell Research & Therapy, Volume 12, pp 1-11; doi:10.1186/s13287-021-02385-8

Abstract:
Background The complications caused by diabetes mellitus (DM) are the focus of clinical treatment. However, little is known about diabetic enteropathy (DE) and its potential underlying mechanism. Methods Intestinal epithelial cells (IECs) and intestinal epithelial stem cells (IESCs) were harvested from BKS.Cg-Dock7m+/+Leprdb/JNju (DM) mice, and the expression of R-Spondin 3 (Rspo3) was detected by RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. The role of Rspo3 in the abnormal differentiation of IECs during DM was confirmed by knockdown experiments. Through miRNA expression profiling, bioinformatics analysis, and RT-qPCR, we further analyzed the differentiation-related miRNAs in the IECs from mice with DM. Results Abnormal differentiation of IECs was observed in the mice with DM. The expression of Rspo3 was upregulated in the IECs from the mice with DM. This phenomenon was associated with Rspo3 overexpression. Additionally, Rspo3 is a major determinant of Lgr5+ stem cell identity in the diabetic state. Microarray analysis, bioinformatics analysis, and luciferase reporter assays revealed that microRNA (miR)-380-5p directly targeted Rspo3. Moreover, miR-380-5p upregulation was observed to attenuate the abnormal differentiation of IECs by regulating Rspo3 expression. Conclusions Together, our results provide definitive evidence of the essential role of Rspo3 in the differentiation of IECs in DM.
Luca Dalle Carbonare, Jessica Bertacco, Giulia Marchetto, Samuele Cheri, Michela Deiana, Arianna Minoia, Natascia Tiso, Monica Mottes,
Stem Cell Research & Therapy, Volume 12, pp 1-12; doi:10.1186/s13287-021-02396-5

Abstract:
Background Methylsulfonylmethane (MSM) is a nutraceutical compound which has been indicated to counteract osteoarthritis, a cartilage degenerative disorder. In addition, MSM has also been shown to increase osteoblast differentiation. So far, few studies have investigated MSM role in the differentiation of mesenchymal stem cells (MSCs), and no study has been performed to evaluate its overall effects on both osteogenic and chondrogenic differentiation. These two mutually regulated processes share the same progenitor cells. Methods Therefore, with the aim to evaluate the effects of MSM on chondrogenesis and osteogenesis, we analyzed the expression of SOX9, RUNX2, and SP7 transcription factors in vitro (mesenchymal stem cells and chondrocytes cell lines) and in vivo (zebrafish model). Real-time PCR as well Western blotting, immunofluorescence, and specific in vitro and in vivo staining have been performed. Student’s paired t test was used to compare the variation between the groups. Results Our data demonstrated that MSM modulates the expression of differentiation-related genes both in vitro and in vivo. The increased SOX9 expression suggests that MSM promotes chondrogenesis in treated samples. In addition, RUNX2 expression was not particularly affected by MSM while SP7 expression increased in all MSM samples/model analyzed. As SP7 is required for the final commitment of progenitors to preosteoblasts, our data suggest a role of MSM in promoting preosteoblast formation. In addition, we observed a reduced expression of the osteoclast-surface receptor RANK in larvae and in scales as well as a reduced pERK/ERK ratio in fin and scale of MSM treated zebrafish. Conclusions In conclusion, our study provides new insights into MSM mode of action and suggests that MSM is a useful tool to counteract skeletal degenerative diseases by targeting MSC commitment and differentiation.
Dingding Yu, Yiming Zhao, , Dejun Kong, Wang Jin, Yonghao Hu, Yafei Qin, Baoren Zhang, Xiang Li, Jingpeng Hao, et al.
Stem Cell Research & Therapy, Volume 12, pp 1-18; doi:10.1186/s13287-021-02392-9

Abstract:
Background Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1β-primed ERCs in the attenuation of experimental colitis. Methods BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 μL), ERCs, and IL-1β-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v.) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction. Results It was found that IL-1β-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2 cells, CD4+CD25+FOXP3+ regulatory T cells (Tregs), and CD68+CD206+ macrophages in spleens were also significantly upregulated in the IL-1β-primed ERC-treated group (p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1β-primed ERC-treated group (p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1β pre-stimulation (p < 0.05) and a higher expression of β-catenin in colonic and splenic tissues after the administration of IL-1β-primed ERCs. Conclusions This study has demonstrated that IL-1β pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/β-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1β-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.
Haiwei Ni, Hai Qin, Cheng Sun, Yichen Liu, Guojing Ruan, Qianqian Guo, , ,
Stem Cell Research & Therapy, Volume 12, pp 1-17; doi:10.1186/s13287-021-02394-7

Abstract:
Background Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness. Methods Lentivirus infection was used to construct GC cells with ectopic expression of miR-375. In vitro and in vivo experiments, including analysis of tumor spheroid formation, CD44+ sub-population with stemness, stemness marker expression, and tumor-initiating ability, were performed to evaluate the effects of miR-375 on the stemness of GC cells. Furthermore, microarray and bioinformatics analysis were performed to search the potential targets of miR-375 in GC cells. Luciferase reporter, RNA immunoprecipitation, and RNA-FISH assays were carried out to verify the targeting of miR-375. Subsequently, combined with tissue microarray analysis, erastin-resistant GC cells, transmission electron microscopy, a series of agonists and oxidative stress markers, the underlying mechanisms contributing to miR-375-mediated effects were explored. Results MiR-375 reduced the stemness of GC cells in vitro and in vivo. Mechanistically, SLC7A11 was identified as a direct target of miR-375 and miR-375 attenuated the stemness of GC cells mainly through triggering SLC7A11-dependent ferroptosis. Conclusion MiR-375 can trigger the ferroptosis through targeting SLC7A11, which is essential for miR-375-mediated inhibition on GC cell stemness. These results suggest that the miR-375/SLC7A11 regulatory axis could serve as a potential target to provoke the ferroptosis and thus attenuate the stemness of GC cells.
, Luis Rodriguez-Menocal, Wellington Guzman, Aisha Khan, Ciara Myer, Xiaochen Liu, Sanjoy K. Bhattacharya,
Stem Cell Research & Therapy, Volume 12, pp 1-11; doi:10.1186/s13287-021-02405-7

Abstract:
Background Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown therapeutic potential in various in vitro and in vivo studies in cutaneous wound healing. Furthermore, there are ubiquitous studies highlighting the pro-regenerative effects of BM-MSC extracellular vesicles (BM-MSC EVs). The similarities and differences in BM-MSC EV cargo among potential healthy donors are not well understood. Variation in EV protein cargo is important to understand, as it may be useful in identifying potential therapeutic applications in clinical trials. We hypothesized that the donors would share both important similarities and differences in cargo relating to cell proliferation, angiogenesis, Wnt signaling, and basement membrane formation—processes shown to be critical for effective cutaneous wound healing. Methods We harvested BM-MSC EVs from four healthy human donors who underwent strict screening for whole bone marrow donation and further Good Manufacturing Practices-grade cell culture expansion for candidate usage in clinical trials. BM-MSC EV protein cargo was determined via mass spectrometry and Proteome Discoverer software. Corresponding proteomic networks were analyzed via the UniProt Consortium and STRING consortium databases. Results More than 3000 proteins were identified in each of the donors, sharing > 600 proteins among all donors. Despite inter-donor variation in protein identities, there were striking similarities in numbers of proteins per biological functional category. In terms of biologic function, the proteins were most associated with transport of ions and proteins, transcription, and the cell cycle, relating to cell proliferation. The donors shared essential cargo relating to angiogenesis, Wnt signaling, and basement membrane formation—essential processes in modulating cutaneous wound repair. Conclusions Healthy donors of BM-MSC EVs contain important similarities and differences among protein cargo that may play important roles in their pro-regenerative functions. Further studies are needed to correlate proteomic signatures to functional outcomes in cutaneous repair.
Stem Cell Research & Therapy, Volume 12, pp 1-16; doi:10.1186/s13287-021-02400-y

Abstract:
Background Systemic sclerosis (SSc) is a disease that features severe fibrosis of the skin and lacks effective therapy. Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) are potential stem cell-based tools for the treatment of SSc. Methods BMSCs were isolated from the bone marrow of mice and identified with surface markers according to multilineage differentiation. EVs were isolated from the BMSC culture medium by ultracentrifugation and identified with a Nanosight NS300 particle size analyzer, transmission electron microscopy (TEM), and western blot. The microRNAs (miRNAs) of BMSC-derived EVs (BMSC-EVs) were studied via miRNA sequencing (miRNA-seq) and bioinformatic analysis. An SSc mouse model was established via subcutaneous bleomycin (BLM) injection, and the mice were treated with BMSCs or BMSC-derived EVs. Skin tissues were dissociated and analyzed with H&E staining, RNA sequencing (RNA-seq), western blot, and immunohistochemical staining. Results Evident pathological changes, like fibrosis and inflammation, were induced in the skin of BLM-treated mice. BMSCs and BMSC-EVs effectively intervened such pathological manifestations and disease processes in a very similar way. The effects of the BMSC-EVs were found to be caused by the miRNAs they carried, which were proven to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple EV-related biological processes. Furthermore, TGF-β1-positive cells and α-SMA-positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice but evidently reduced in the scleroderma skin of the EV-treated SSc group. In addition, the numbers of mast cells and infiltrating macrophages and lymphocytes were evidently increased in the skin of BLM-treated mice but significantly reduced by EV treatment. In line with these observations, there were significantly higher mRNA levels of the inflammatory cytokines Il6, Il10, and Tnf-α in SSc mice than in control mice, but the levels decreased following EV treatment. Through bioinformatics analysis, the TGFβ and WNT signaling pathways were revealed to be closely involved in the pathogenic changes seen in mouse SSc, and these pathways could be therapeutic targets for treating the disease. Conclusions BMSC-derived EVs could be developed as a potential therapy for treating skin dysfunction in SSc, especially considering that they show similar efficacy to BMSCs but have fewer developmental regulatory requirements than cell therapy. The effects of EVs are generated by the miRNAs they carry, which alleviate SSc pathogenic changes by regulating the WNT and TGFβ signaling pathways.
Ruijie Zeng, Jinghua Wang, Zewei Zhuo, Yujun Luo, ,
Stem Cell Research & Therapy, Volume 12, pp 1-14; doi:10.1186/s13287-021-02389-4

Abstract:
Necrotizing enterocolitis (NEC) is a devastating disease predominately affecting neonates. Despite therapeutic advances, NEC remains the leading cause of mortality due to gastrointestinal conditions in neonates. Stem cells have been exploited in various diseases, and the application of different types of stem cells in the NEC therapy is explored in the past decade. However, stem cell transplantation possesses several deficiencies, and exosomes are considered potent alternatives. Exosomes, especially those derived from stem cells and breast milk, demonstrate beneficial effects for NEC both in vivo and in vitro and emerge as promising options for clinical practice. In this review, the function and therapeutic effects of stem cells and exosomes for NEC are investigated and summarized, which provide insights for the development and application of novel therapeutic strategies in pediatric diseases. Further elucidation of mechanisms, improvement in preparation, bioengineering, and administration, as well as rigorous clinical trials are warranted.
Hyun-Ji Lee, , Da-Won Choi, Kyung-Ah Cho, Joo-Won Park, Sang-Jin Shin, Inho Jo, So-Youn Woo,
Stem Cell Research & Therapy, Volume 12, pp 1-13; doi:10.1186/s13287-021-02414-6

Abstract:
Background Co-transplantation of bone marrow cells (BMCs) and mesenchymal stem cells (MSCs) is used as a strategy to improve the outcomes of bone marrow transplantation. Tonsil-derived MSCs (TMSCs) are a promising source of MSCs for co-transplantation. Previous studies have shown that TMSCs or conditioned media from TMSCs (TMSC-CM) enhance BMC engraftment. However, the factors in TMSCs that promote better engraftment have not yet been identified. Methods Mice were subjected to a myeloablative regimen of busulfan and cyclophosphamide, and the mRNA expression in the bone marrow was analyzed using an extracellular matrix (ECM) and adhesion molecule-targeted polymerase chain reaction (PCR) array. Nano-liquid chromatography with tandem mass spectrometry, real-time quantitative PCR, western blots, and enzyme-linked immunosorbent assays were used to compare the expression levels of metalloproteinase 3 (MMP3) in MSCs derived from various tissues, including the tonsils, bone marrow, adipose tissue, and umbilical cord. Recipient mice were conditioned with busulfan and cyclophosphamide, and BMCs, either as a sole population or with control or MMP3-knockdown TMSCs, were co-transplanted into these mice. The effects of TMSC-expressed MMP3 were investigated. Additionally, Enzchek collagenase and Transwell migration assays were used to confirm that the collagenase activity of TMSC-expressed MMP3 enhanced BMC migration. Results Mice subjected to the myeloablative regimen exhibited increased mRNA expression of collagen type IV alpha 1/2 (Col4a1 and Col4a2). Among the various extracellular matrix-modulating proteins secreted by TMSCs, MMP3 was expressed at higher levels in TMSCs than in other MSCs. Mice co-transplanted with BMCs and control TMSCs exhibited a higher survival rate, weight recovery, and bone marrow cellularity compared with mice co-transplanted with BMCs and MMP3-knockdown TMSCs. Control TMSC-CM possessed higher collagenase activity against collagen IV than MMP3-knockdown TMSC-CM. TMSC-CM also accelerated BMC migration by degrading collagen IV in vitro. Conclusions Collectively, these results indicate that TMSCs enhance BMC engraftment by the secretion of MMP3 for the modulation of the bone marrow extracellular matrix.
Catalina-Iolanda Marinescu, Mihai Bogdan Preda,
Stem Cell Research & Therapy, Volume 12, pp 1-13; doi:10.1186/s13287-021-02344-3

Abstract:
Background Mesenchymal stem/stromal cells (MSC) represent adult cells with multipotent capacity. Besides their capacity to differentiate into multiple lineages in vitro and in vivo, increasing evidence points towards the immunomodulatory capacity of these cells, as an important feature for their therapeutic power. Although not included in the minimal criteria established by the International Society for Cellular Therapy as a defining MSC attribute, demonstration of the immunomodulatory capacity of MSC can be useful for the characterization of these cells before being considered MSC. Methods Here we present a simple and reliable protocol by which the immunosuppressive effect of mouse bone marrow-derived MSC can be evaluated in vitro. It is based on the measuring of the proliferation of activated T cells cultured in direct contact with irradiated MSC. Results Our results showed that mouse MSC have a dose-dependent inhibitory effect on activated T cell proliferation, which can be quantified as a percentage of maximum proliferation. Our data shows that batch-to-batch variability can be determined within one or multiple experiments, by extracting the area under curve of T cell proliferation plotted against the absolute number of MSC in co-culture. Conclusions The validation of the immunosupressive capacity of MSC could be added to the characterization of the cells before being used in various MSC-based approaches to treat immunological diseases. Our results showed that mouse MSC have a dose-dependent inhibitory effect on activated T cell proliferation. The immunosuppressive properties of MSC vary between batches, but not between different passages of the same batch.
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