Stem Cell Research & Therapy最新文献

{"title":"Single-cell transcriptomics of clinical grade adipose-derived regenerative cells reveals consistency between donors independent of gender and BMI.","authors":"Frederik Adam Bjerre, Jakob Vennike Nielsen, Mark Burton, Pratibha Dhumale, Mads Gustaf Jørgensen, Sabrina Toft Hansen, Lars Lund, Mads Thomassen, Jens Ahm Sørensen, Ditte Caroline Andersen, Charlotte Harken Jensen","doi":"10.1186/s13287-025-04234-4","DOIUrl":"10.1186/s13287-025-04234-4","url":null,"abstract":"<p><p>Adipose-derived regenerative cells (ADRCs) also referred to as the stromal vascular fraction, provide an ample source of stem cells with widespread regenerative therapeutic use. Being heterogenous in nature, possibly affecting the clinical outcome after stem cell treatment, the ADRC- donor, -BMI, and -gender may have a large impact on ADRC composition and quality but this remains largely unexplored. Herein, we provide a comprehensive single-cell RNA sequencing ADRC mapping across two cell trial intervention studies but found no gender- or BMI-related variations, except for a minor female increase in PI16/CD55-expressing stem cells. Indeed, ADRC heterogeneity was surprisingly minimal between donors. This provides important decision-making support on adipose stem cell donor selection for stem cell treatments, and suggest that donor, gender and BMI should be regarded as less influential.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"109"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of intra-articular applied rat BMSCs expressing alpha-calcitonin gene-related peptide or substance P on osteoarthritis pathogenesis in a murine surgical osteoarthritis model.","authors":"Sabine Stöckl, Shahed Taheri, Verena Maier, Amir Asid, Martina Toelge, Hauke Clausen-Schaumann, Arndt Schilling, Susanne Grässel","doi":"10.1186/s13287-025-04155-2","DOIUrl":"10.1186/s13287-025-04155-2","url":null,"abstract":"<p><strong>Background: </strong>About 655 million persons worldwide are affected by osteoarthritis (OA). As no therapy modifies disease progression long-term, there is an immense clinical need for novel therapies. The joints are innervated by alpha calcitonin gene-related peptide (αCGRP)- and substance P (SP)-positive sensory nerve fibers. Both neuropeptides have trophic effects on target cells within the joints. The aim of this study was to examine the effects of SP- and αCGRP-expressing intra-articular (i.a.) applied rat(r)BMSC on cartilage and subchondral bone structural changes after OA induction.</p><p><strong>Methods: </strong>Mice were subjected to destabilization of the medial meniscus (DMM) surgery, followed by i.a. injections with rBMSC, transduced with lacZ, SP or αCGRP. 2, 8 and 16 weeks after DMM/Sham surgery, motion analysis and serum marker analysis were performed. Cartilage and subchondral bone properties were assessed by OA scoring, atomic force microscopy and nano-CT analysis.</p><p><strong>Results: </strong>OARSI scores of the medial cartilage compartments indicated induction and progression of OA after DMM surgery in all groups. Differences between the treatment groups were mostly restricted to the lateral cartilage compartments, where αCGRP caused a decrease of structural changes. DMM-rBMSC-αCGRP or -SP mice displayed decreased cartilage stiffness in the cartilage middle zone. DMM-rBMSC-αCGRP mice revealed improved mobility, whereas Sham-rBMSC-SP mice revealed reduced mobility compared to rBMSC-lacZ. With respect to condyle length, subarticular bone and ephiphyseal bone morphology, DMM-rBMSC-SP mice had more alterations indicating either a more progressed OA stage or a more severe OA pathology compared to controls. In addition, DMM-rBMSC-SP mice developed osteophytes already 8 weeks after surgery. Adiponectin serum level was increased in DMM-rBMSC-αCGRP mice, and MIP1b level in DMM-rBMSC-SP mice. Notably, pain and inflammation markers increased over time in rBMSC-SP mice while rBMSC-αCGRP mice revealed a bell-shaped curve with a peak at 8 weeks.</p><p><strong>Conclusions: </strong>We conclude that i.a. injection of rBMSC in general have a beneficial effect on cartilage matrix structure, subchondral bone microarchitecture and inflammation. rBMSC-αCGRP have anabolic and possible analgesic properties and may attenuate the progression or severity of OA. In contrast, rBMSC-SP exert a more catabolic influence on knee joints of both, Sham and DMM mice, making it a potential candidate for inhibition studies.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"117"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid droplet-free nanovesicles extruded from stromal vascular fraction improve adipocyte regeneration in the centre of dermal graft.","authors":"Yuyang Zeng, Di Sun, Rongrong Wang, Ran An, Jiaming Sun, Jie Yang","doi":"10.1186/s13287-025-04240-6","DOIUrl":"10.1186/s13287-025-04240-6","url":null,"abstract":"<p><strong>Background: </strong>The stromal vascular fraction (SVF) has been validated for enhancing tissue regeneration because of its concentration of multipotent cells and growth factors, and for mitigating inflammatory response due to its elimination of the majority of lipid droplets. However, it is difficult for fresh SVF to maintain bioactivity for a long period, and the loss of numerous tangible masses during preparation limits its application in repairing large volume defects. Here, we fabricated a self-assembly nanovesicle extruded from SVF (SVF-EVs) by mechanical shear and co-transplanted it with dermal microparticles to verify its potential for repairing large volume defects.</p><p><strong>Methods: </strong>The SVF-EVs were prepared by removing the oil from adipose tissue followed by sequentially extruding SVF through membrane filters. The lipid content of SVF-EVs was compared with SVF using Oil Red O staining. The morphology and adipogenic-related protein of SVF-EVs were characterized. The pro-adipogenic potency of SVF-EVs in vitro was determined using Oil Red O staining of ADSCs, western blot, and qRT-PCR. In vivo, dermal particle grafts mixed with SVF-EVs were subcutaneously transplanted in nude mice and harvested after 4 and 6 weeks. By examining the weight and volume of grafts and histological staining, we explored the effect of SVF-EVs on adipose tissue regeneration and anti-inflammatory ability.</p><p><strong>Results: </strong>Our results showed that the removal rate of proceeding of SVF-EVs could remove 75.07 ± 2.80% lipid in SVF. The SVF-EVs displayed 100 ~ 150 nm sphere vesicles and contained pro-adipogenic protein. In vitro, SVF-EVs promote the synthesis of lipids in ADSCs. Besides, after co-transplanting of SVF-EVs, adipose regeneration was detected in vivo in the dermal particle grafts.</p><p><strong>Conclusions: </strong>These findings revealed that extruding SVF into nanovesicles can effectively reduce the implantation of lipid droplets that cause inflammation, and co-transplanting SVF-EVs with dermal microparticles may be a considerable strategy for large volume defects repair.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"114"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX₃CR1⁺ synovial lining macrophage barrier.","authors":"Lei Wang, Ming Hao, Yongyue Xu, Zhaoyan Wang, Hanqi Xie, Bo Zhang, Xue Zhang, Jun Lin, Xiaodan Sun, Jianbin Wang, Qiong Wu","doi":"10.1186/s13287-025-04144-5","DOIUrl":"10.1186/s13287-025-04144-5","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is a chronic autoimmune disease and the integrity of CX₃CR1⁺ synovial macrophage barrier significantly impacts its progression. However, the mechanisms driving the dynamic changes of this macrophage barrier remain unclear. Traditional drug therapies for RA have substantial limitations. Mesenchymal stem cells (MSCs)-based cell therapy, especially adipose-derived stem cells (ADSCs), hold therapeutic promise. Nevertheless, the underlying therapeutic mechanism of ADSCs, especially their interactions with CX₃CR1⁺ macrophages, require further investigation.</p><p><strong>Methods: </strong>To explore the interaction between ADSCs and CX₃CR1⁺ synovial macrophages during barrier reconstruction, underlying the therapeutic mechanism of ADSCs and the mechanisms on the dynamic changes of the macrophage barrier, scRNA-seq analysis was conducted 4 days after ADSCs injection in serum transfer-induced arthritis model mice. The roles of mitochondria transfer and ADSCs transplantation were also explored. Bulk RNA-seq analysis was performed after the co-culture of ADSCs and CX₃CR1⁺ synovial macrophages. To study the in vivo fate of ADSCs, bulk RNA-seq was performed on ADSCs retrieved at 0, 2, 4, and 7 days post-injection.</p><p><strong>Results: </strong>Intra-articular injection of ADSCs effectively attenuated the pathological progression of mice with serum transfer-induced arthritis. ADSCs gradually adhered to CX₃CR1⁺ macrophages, facilitating the restore of the macrophage barrier, while the absence of this barrier greatly weakened the therapeutic effect of ADSCs. scRNA-seq analysis revealed an Atf3^high Ccl3^high subset of CX₃CR1⁺ macrophages with impaired oxidative phosphorylation that increased during RA progression. ADSCs-mediated reduction of this subset appeared to be linked to mitochondrial transfer, and transplantation of isolated ADSCs-derived mitochondria also proved effective in treating RA. Both bulk RNA-seq and scRNA-seq analyses revealed multiple interaction mechanisms between ADSCs and CX₃CR1⁺ macrophages, including Cd74/Mif axis and GAS6/MERTK axis, which contribute to barrier restoration and therapeutic effects. Furthermore, bulk RNA-seq analysis showed that ADSCs primarily contribute to tissue repair and immune regulation subsequently.</p><p><strong>Conclusions: </strong>Our results suggest that ADSCs ameliorated the energy metabolism signature of CX₃CR1⁺ lining macrophages and may promote barrier restoration through mitochondria transfer. In addition, we elucidated the fate of ADSCs and the therapeutic potential of mitochondria in RA treatment.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"111"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal miR-125b-5p derived from mesenchymal stromal/stem cell enhances anti-PD-1 therapy in mouse colon cancer model.","authors":"Mengmeng Jiang, Jia Liu, Shengquan Hu, Xueqin Yan, Yongkai Cao, Zhengzhi Wu","doi":"10.1186/s13287-025-04227-3","DOIUrl":"10.1186/s13287-025-04227-3","url":null,"abstract":"<p><strong>Background: </strong>There is compelling evidence that FoxP3⁺ regulatory T cells (Tregs) play a critical role in promoting tumor immune evasion. Our prior research demonstrated that the expression of miR-125b-5p directly inhibits Tregs by targeting TNFR2 and FoxP3. Given the significant therapeutic potential of mesenchymal stromal/stem cell (MSC)-derived exosomes (MSC-EXO) in cancer treatment, the potential role of MSC-EXO in augmenting anti-tumor immunotherapy through the delivery of miR-125b-5p remains unexplored.</p><p><strong>Methods: </strong>Nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were employed to characterize exosomes derived from MSCs. Flow cytometry analysis was conducted to investigate the function of exosomal miR-125b-5p both in vitro and in vivo. Mouse MC38 tumor models were administrated MSC-derived exosomes containing miR-125b-5p via tail vein injection, with or without the concurrent injection (intraperitoneally, i.p.) of anti-PD-1 antibodies.</p><p><strong>Results: </strong>Our results indicated that exosomal miR-125b-5p derived from MSC significantly inhibited the expansion, proliferation and suppressive function of Tregs in vitro. Moreover, we observed a marked reduction in tumor growth in mice treated with exosomal miR-125b-5p. Notably, while anti-PD-1 therapy alone achieved a cure rate of approximately 30% in a mouse model of colon cancer, the combined administration of exosomal miR-125b-5p significantly enhanced the therapeutic efficacy, resulting in a more than two- to three-fold increase in tumor regression in approximately 80% of the treated mice. The underlying cellular mechanism was closely associated with the reduction of tumor-infiltrating Tregs. and the increase of CD8⁺ cytotoxic T lymphocytes (CTLs).</p><p><strong>Conclusions: </strong>In summary, our findings suggest that exosomal miR-125b-5p derived from MSC exerts prominent potential in advancing anti-PD-1 therapy by modulating tumor immune environment. This property of miR-125b-5p may be therapeutically harnessed in human cancers to enhance the efficacy of immunotherapy.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"112"},"PeriodicalIF":7.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptotic vesicles derived from bone marrow mesenchymal stem cells increase angiogenesis in a hind limb ischemia model via the NAMPT/SIRT1/FOXO1 axis.","authors":"Jinxing Chen, Zekun Shen, Bingyi Chen, Shuang Liu, Yifan Mei, Kai Li, Ziyang Peng, Chaoshuai Feng, Weiyi Wang, Shaoying Lu","doi":"10.1186/s13287-025-04245-1","DOIUrl":"10.1186/s13287-025-04245-1","url":null,"abstract":"<p><strong>Background: </strong>Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral arterial disease (PAD). Mesenchymal stem cell (MSC) transplantation holds promise as a treatment for CLTI; however, the harsh local environment poses challenges to its effectiveness. Apoptotic vesicles (ApoVs) are extracellular vesicles produced by cells undergoing apoptosis, and they can carry various biomolecules from their parent cells, including proteins, RNA, DNA, lipids, ions, and gas neurotransmitters. ApoVs play significant roles in anti-inflammatory responses, anti-tumor activities, and tissue regeneration through intercellular communication, and they have demonstrated potential as drug carriers. In this study, we investigated the potential of bone marrow stem cell (BMSC)-derived ApoVs for treating CLTI.</p><p><strong>Methods: </strong>In vivo, we explored the therapeutic effect of ApoVs on a hindlimb ischemia model through Laser Doppler, matrigel plug assay, and histological analysis. In vitro, we analyzed the effects of ApoVs on the proliferation, migration, and angiogenesis of HUVECs and explored the uptake process of ApoVs. In addition, Proteomic analysis, western blotting, quantitative real-time PCR, shRNA, and siRNA were used to analyze ApoVs-induced HUVECs activation and downstream signaling pathways.</p><p><strong>Results: </strong>BMSCs transplantation showed improvement in a hind limb ischemia model, and this effect still exists after apoptosis of BMSCs. Subsequently, ApoVs of BMSCs were isolated and found to improve mouse hind limb ischemia in vivo. In vitro, ApoVs can be ingested by HUVECs through dynamin-, clathrin-, and caveolin-mediated endocytosis and promote its proliferation, migration, and angiogenesis. Mechanistically, ApoVs transferred NAMPT to HUVECs, therefore activating the NAMPT/SIRT1/FOXO1 axis, influencing the transcriptional activity of FOXO1, and promoting angiogenesis.</p><p><strong>Conclusions: </strong>Our results demonstrate that the transplanted BMSCs can ameliorate hindlimb ischemia by releasing ApoVs during apoptosis. The main mechanism of this effect is promoting the proliferation, migration, and angiogenesis of HUVECs through the NAMPT/SIRT1/FOXO1 axis. This study provides different insights into the therapeutic mechanisms through BMSCs and suggests a promising direction for ApoVs transplantation.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"105"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of oxidative stress-mediated fibro-adipogenic progenitor senescence in skeletal muscle regeneration and repair.","authors":"Yuqing Yao, Yusheng Luo, Xiaomei Liang, Li Zhong, Yannan Wang, Zhengchao Hong, Chao Song, Zeyu Xu, Jiancheng Wang, Miao Zhang","doi":"10.1186/s13287-025-04242-4","DOIUrl":"10.1186/s13287-025-04242-4","url":null,"abstract":"<p><strong>Background: </strong>Stem cells play a pivotal role in tissue regeneration and repair. Skeletal muscle comprises two main stem cells: muscle stem cells (MuSCs) and fibro-adipogenic progenitors (FAPs). FAPs are essential for maintaining the regenerative milieu of muscle tissue and modulating the activation of muscle satellite cells. However, during acute skeletal muscle injury, the alterations and mechanisms of action of FAPs remain unclear.</p><p><strong>Methods: </strong>we employed the GEO database for bioinformatics analysis of skeletal muscle injury. A skeletal muscle injury model was established through cardiotoxin (CTX, 10µM, 50µL) injection into the tibialis anterior (TA) of C57BL/6 mice. Three days post-injury, we extracted the TA, isolated FAPs (CD31^-CD45^-PDGFRα⁺Sca-1⁺), and assessed the senescence phenotype through SA-β-Gal staining and Western blot. Additionally, we established a co-culture system to evaluate the capacity of FAPs to facilitate MuSCs differentiation. Finally, we alleviated the senescent of FAPs through in vitro (100 µM melatonin, 5 days) and in vivo (20 mg/kg/day melatonin, 15 days) administration experiments, confirming melatonin's pivotal role in the regeneration and repair processes of skeletal muscle.</p><p><strong>Results: </strong>In single-cell RNA sequencing analysis, we discovered the upregulation of senescence-related pathways in FAPs following injury. Immunofluorescence staining revealed the co-localization of FAPs and senescent markers in injured muscles. We established the CTX injury model and observed a reduction in the number of FAPs post-injury, accompanied by the manifestation of a senescent phenotype. Melatonin treatment was found to attenuate the injury-induced senescence of FAPs. Further co-culture experiments revealed that melatonin facilitated the restoration of FAPs' capacity to promote myoblast differentiation. Through GO and KEGG analysis, we found that the administration of melatonin led to the upregulation of AMPK pathway in FAPs, a pathway associated with antioxidant stress response. Finally, drug administration experiments corroborated that melatonin enhances skeletal muscle regeneration and repair by alleviating FAP senescence in vivo.</p><p><strong>Conclusion: </strong>In this study, we first found FAPs underwent senescence and redox homeostasis imbalance after injury. Next, we utilized melatonin to enhance FAPs regenerative and repair capabilities by activating AMPK signaling pathway. Taken together, this work provides a novel theoretical foundation for treating skeletal muscle injury.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"104"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of phenotypically stable and functionally mature human bone marrow MSCs derived Schwann cells via the induction of human iPSCs-derived sensory neurons.","authors":"Yu Pan, Haohui Lin, Manhon Chung, Yi Yang, Li Zhang, Xiaohua Pan, Sa Cai","doi":"10.1186/s13287-025-04217-5","DOIUrl":"10.1186/s13287-025-04217-5","url":null,"abstract":"<p><strong>Background: </strong>Phenotypically unstable Schwann cell-like cells (SCLCs), derived from mesenchymal stem cells (MSCs) require intercellular contact-mediated cues for Schwann cell (SCs)-fate commitment. Although rat dorsal root ganglion (DRG) neurons provide contact-mediated signals for the conversion of SCLCs into fate-committed SCs, the use of animal cells is clinically unacceptable. To overcome this problem, we previously acquired human induced pluripotent stem cell-derived sensory neurons (hiPSC-dSNs) as surrogates of rat DRG neurons that committed rat bone marrow SCLCs to the SC fate. In this study, we explored whether hiPSC-dSNs could mimic rat DRG neuron effects to obtain fate-committed SCs from hBMSC-derived SCLCs.</p><p><strong>Methods: </strong>hiPSCs were induced into hiPSC-dSNs using a specific chemical small molecule combination. hBMSCs were induced into hBMSC-derived SCLCs in a specific culture medium and then co-cultured with hiPSC-dSNs to generate SCs. The identity of hBMSC-derived SCs (hBMSC-dSCs) was examined by immunofluorescence, western bolt, electronic microscopy, and RNA-seq. Immunofluorescence was also used to detect the myelination capacity. Enzyme-linked immunosorbent assay and neurite outgrowth analysis were used to test the secretion of neurotrophic factors.</p><p><strong>Results: </strong>The hBMSC-dSCs exhibited bi-/tri-polar morphology of SCs and maintained the expression of the SC markers S100, p75NTR, p0, GFAP, and Sox10, even after withdrawing the glia-inducing factors or hiPSC-dSNs. Electronic microscopy and RNA-seq analysis provided evidence that hBMSC-dSCs were similar to the original human SCs in terms of their function and a variety of characteristics. Furthermore, these cells formed MBP-positive segments and secreted neurotrophic factors to facilitate the neurite outgrowth of Neuro2A.</p><p><strong>Conclusions: </strong>These results demonstrated that phenotypically stable and functionally mature hBMSC-dSCs were generated efficiently via the co-culture of hiPSC-dSNs and hBMSC-derived SCLCs. Our findings may provide a promising protocol through which stable and fully developed hBMSC-dSCs can be used for transplantation to regenerate myelin sheath.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"106"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of circALPK2 enhances proliferation and therapeutic potential of human pluripotent stem cell-derived cardiomyocytes in myocardial infarction.","authors":"Hongchun Wu, Xue Jiang, Hao Fan, Jingjing Li, Yuan Li, Yingjiong Lin, Dandan Zhao, Xinglong Han, Miao Yu, Jun-Ming Tang, Shijun Hu, Wei Lei","doi":"10.1186/s13287-025-04230-8","DOIUrl":"10.1186/s13287-025-04230-8","url":null,"abstract":"<p><strong>Background: </strong>Understanding the mechanisms regulating human cardiomyocyte proliferation holds significant promise for developing effective therapies to enhance cardiac regeneration and repair. This study investigates the role of circALPK2, a circular RNA derived from the back-splicing of the 4th exon of alpha protein kinase 2 (ALPK2), in regulating cardiomyocyte proliferation and its therapeutic efficacy in myocardial infarction (MI) treatment.</p><p><strong>Methods: </strong>Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were used to assess the expression and function ofcircALPK2. Lentiviral shRNA-mediated knockdown of circALPK2 was performed in hESC-CMs, followed by RNA sequencing to identify targeted genes and biological processes. The proliferative capacity of wild-type and circALPK2 knockdown hESC-CMs was evaluated using CCK-8 assay, EdU staining and RT-qPCR analysis of cell cycle-related genes. Dual luciferase assays were conducted to validate the predicted miRNA targets and their downstream effects. For in vivo evaluation, MI mice were injected with either wild-type or circALPK2 knockdown hESC-CMs, and the therapeutic potential was assessed by echocardiographic and histological analyses.</p><p><strong>Results: </strong>We identified circALPK2 as a negative regulator of cell proliferation in hESC-CMs. CircALPK2 was abundantly expressed in hESC-CMs. Knockdown of circALPK2 significantly enhanced cell proliferation in hESC-CMs, as demonstrated by CCK-8 assays (p < 0.001) and EdU staining (p < 0.001), and accelerated the expression of cell cycle-related genes, including CCNA2(p < 0.05) and CDK1 (p < 0.01). Furthermore, circALPK2 was found to function as a sponge to inhibit miR-9 activity, while miR-9 mimics significantly boosted the proliferative capacity of hESC-CMs. Glycogen synthase kinase 3β (GSK3B), a key inhibitor of WNT signaling, was identified as a direct target of miR-9, mediating the regulation of cardiomyocyte proliferation. Importantly, circALPK2 knockdown improved the myocardial repair potential of hESC-CMs when injected into infarcted mouse hearts, as indicated by improved left ventricular ejection fraction (p < 0.01) and fractional shortening (p < 0.05).</p><p><strong>Conclusions: </strong>Our study identifies the circALPK2/miR-9/GSK3B axis as a novel target for promoting cardiomyocyte proliferation and enhancing cardiac regeneration.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"107"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cells alleviate idiopathic pneumonia syndrome by facilitating M2 polarization via CCL2/CCR2 axis and further inducing formation of regulatory CCR2 + CD4 + T cells.","authors":"Chao Xue, Wei Liu, Yuan Li, Yue Yin, Bo Tang, Jinye Zhu, Yujun Dong, Huihui Liu, Hanyun Ren","doi":"10.1186/s13287-025-04232-6","DOIUrl":"10.1186/s13287-025-04232-6","url":null,"abstract":"<p><strong>Background: </strong>Our previous study revealed that mesenchymal stem cells (MSCs) can secrete large amounts of the chemokine CCL2 under inflammatory conditions and alleviate idiopathic pneumonia syndrome (IPS) by promoting regulatory CCR2 + CD4 + T-cell formation through the CCL2‒CCR2 axis. Given the abundance of macrophages in lung tissue, how these macrophages are regulated by MSC-based prophylaxis via IPS and their interactions with T cells in lung tissue during allo-HSCT are still not fully understood.</p><p><strong>Methods: </strong>An IPS mouse model was established, and MSC-based prophylaxis was administered. In vitro coculture systems and an IPS model were used to study the interactions among MSCs, macrophages and T cells.</p><p><strong>Results: </strong>Prophylactic administration of MSCs induced M2 polarization and alleviated acute graft-versus-host disease (aGVHD) and lung injury in an IPS mouse model. In vitro coculture studies revealed that M2 polarization was induced by MSC-released CCL2 and that these M2 macrophages promoted the formation of regulatory CCR2 + CD4 + T cells. Blocking the CCL2-CCR2 interaction in vitro reversed MSC-induced M2 polarization and abolished the induction of CCR2 + CD4 + T-cell formation. Additionally, in vivo administration of a CCL2 or CCR2 antagonist in the IPS mouse model exacerbated aGVHD and lung injury, accompanied by a reduction in M2 macrophages and reduced formation of regulatory CCR2 + CD4 + T cells in lung tissue.</p><p><strong>Conclusions: </strong>MSCs alleviate IPS by facilitating M2 polarization via the CCL2‒CCR2 axis and further inducing the formation of regulatory CCR2 + CD4 + T cells.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"108"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}