Stem cells and development最新文献

{"title":"Specifically Enhanced Immunosuppression of B Cells with Chimeric Antigen Receptors Modify Mesenchymal Stem Cells.","authors":"Xiaoyan Zhao, Jingxi Gao, Xingyu Zhu, Yunhua Chen, Hui Ge, Yuzhen Xiao, Qin Han, Zhao Sun, Xiuli Zhao, Robert Chunhua Zhao","doi":"10.1089/scd.2025.0021","DOIUrl":"https://doi.org/10.1089/scd.2025.0021","url":null,"abstract":"<p><p>Recently, cell therapies, including chimeric antigen receptor (CAR) modified T cell therapy and mesenchymal stem cell (MSC) therapy, have demonstrated considerable potential for systemic lupus erythematosus (SLE). In this study, a CAR-MSC model was constructed, combining two cell therapies. The structural domains of the CAR were designed by using the anti-CD19 scFv, targeting the CD19 antigen on the surface of B cells and the intracellular region of the interferon-gamma receptor, activating the JAK-STAT1 signaling pathway. Then we screened and identified the most effective structural domain of CAR as CAR1, as it facilitates MSCs to maintain significantly higher levels of JAK2 phosphorylation and IDO expression, as shown by western blot analysis. We also demonstrated CAR1 could be consistently and stably expressed at high levels in MSCs, and CAR1 transduction did not significantly affect the surface antigenic phenotypic criteria of MSCs via flow analysis. Furthermore, immunofluorescence results showed CAR1-MSCs could stably bind CD19 antigen, and they were activated by human CD19 antigen resulting in significantly high JAK2 phosphorylation and IDO expression via western blot analysis following co-culture. Besides, when activated peripheral blood mononuclear cells (PBMCs) were co-cultured with untransduced MSCs (UTD-MSCs) and CAR1-MSCs in vitro, respectively, the results showed that the percentage of activated CD3⁺ T cells and CD19⁺ B cells was both significantly lower after co-culturing. The percentage of activated CD19⁺ B cells was lower in the CAR1-MSCs co-culture group than in the UTD-MSCs co-culture group, whereas the percentage of activated CD3⁺ T cells was similar in the two co-culture groups. This suggests that CAR1 increased the inhibitory ability of MSCs on activated CD19⁺ B cells and had no significant effect on the ability of MSCs to inhibit activated CD3⁺ T cells. In conclusion, CAR1-MSCs were successfully constructed and demonstrated the ability to enhance the inhibitory effect of MSCs on activated human CD19⁺ B cells, facilitating SLE therapy.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and Opportunities in Translating Extracellular Vesicles into Clinical Applications.","authors":"Ciro Tetta, Giovanni Camussi","doi":"10.1089/scd.2025.0051","DOIUrl":"https://doi.org/10.1089/scd.2025.0051","url":null,"abstract":"","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":"34 9-10","pages":"187-188"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment of Premature Ovarian Failure Mouse Model Using Granulosa-Like Cells Derived from Wharton's Jelly-Mesenchymal Stem Cells.","authors":"Sang-Yun Lee, Dinesh Bharti, Won-Jae Lee, Young-Bum Son, Yeung Bae Jin, Hyeon-Jeong Lee, Chan-Hee Jo, Seong-Ju Oh, Chae-Yeon Hong, Seo-Yoon Kang, Sanghyeon Park, Yong-Ho Choe, Sung-Lim Lee","doi":"10.1089/scd.2025.0027","DOIUrl":"https://doi.org/10.1089/scd.2025.0027","url":null,"abstract":"<p><p>Premature ovarian failure (POF) is a significant reproductive disorder characterized by the loss of ovarian function, leading to infertility and endocrine disruption. Hormone replacement therapy (HRT) remains the most commonly used clinical treatment for POF. However, in patients with a history of ovarian or breast cancer, HRT poses significant risks, necessitating the development of alternative approaches. Stem cell-based therapy has emerged as a promising option for treating female infertility disorders such as POF. This study aimed to evaluate the therapeutic effects of ovarian granulosa-like cells (OGLCs) derived from Wharton's jelly-mesenchymal stem cells (WJ-MSCs) in a POF mouse model. WJ-MSCs were successfully differentiated into OGLCs using combination with a growth factor cocktails, as confirmed by the significant upregulation of granulosa cell-specific markers (<i>P</i> < 0.01). To assess their therapeutic potential, POF was induced in female mice using cyclophosphamide and busulfan, and OGLCs were injected into the ovaries. After 3 weeks, vaginal smear analysis revealed restoration of estrus cycle in OGLC-treated mice. Enzyme-linked immunosorbent assay analysis demonstrated the recovery of serum 17β-estradiol and follicle-stimulating hormone levels (<i>P</i> < 0.05), while histological staining confirmed increased follicular development and restoration of ovarian structure. Furthermore, real-time quantitative polymerase chain reaction analysis showed a significant upregulation of genes related to follicular development and primordial follicle activation, including downstream molecules of the mTOR/PI3K pathway, following OGLCs treatment. These findings suggest that OGLCs possess a strong potential for restoring ovarian function in POF. This study provides evidence supporting the use of OGLCs as a novel cell-based therapeutic approach for female reproductive diseases.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":"34 9-10","pages":"214-225"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Supportive Role of Lymph Node Mesenchymal Stromal Cells in Follicular Lymphoma Involves the PITX1-hTERT-Podoplanin Axis.","authors":"Sumie Fujii, Noriko Sugino, Yasuo Miura","doi":"10.1089/scd.2025.0022","DOIUrl":"10.1089/scd.2025.0022","url":null,"abstract":"<p><p>The microenvironment within lymph nodes plays a pivotal role in the pathogenesis of follicular lymphoma (FL), a malignancy characterized by the accumulation of neoplastic B cells. Here, we report that human FL lymph node mesenchymal stromal cells (FLSCs) display surface protein expression profiles consistent with the standard phenotypic criteria for human mesenchymal stromal/stem cells (MSCs), yet exhibit reduced mesenchymal differentiation capability. FLSCs did not show the typical immunomodulatory protein expression patterns observed in fibroblastic reticular cells, marginal reticular cells, or follicular dendritic cells, as they expressed chemokine (C-X-C motif) ligand 13 and podoplanin but lacked chemokine (C-C motif) ligand 19 and complement receptor 1/2. Functionally, FLSCs exhibited superior FL cell survival-supportive capability in cocultures compared with bone marrow MSCs. This supportive effect was reduced when the cell culture inserts were used. In addition, this supportive capability was accompanied by reduced levels of B-cell-supportive soluble factors such as interleukin-6, regardless of the presence of cell culture inserts. Thus, both cell-cell contact-dependent and -independent mechanisms are involved in this process. Comprehensive transcriptomic analysis revealed that transcription factor paired-like homeodomain 1 (PITX1) is downregulated in FLSCs. Given that PITX1 regulates human telomerase reverse transcriptase (hTERT) transcription, FLSCs exhibited longer telomeres and a higher population-doubling capacity than MSCs. Furthermore, FLSCs expressed elevated podoplanin, whereas MSCs did not. Notably, hTERT-transfected MSCs also showed increased podoplanin expression, suggesting a positive association between hTERT and podoplanin. In summary, our findings indicate that FLSCs deviate from classical MSCs in their differentiation potential and instead exhibit a protumorigenic phenotype. This phenotype supports FL cell survival and is potentially mediated by an aberrant PITX1-hTERT-podoplanin signaling axis. These results highlight the critical role of FLSCs in the FL lymph node microenvironment, with implications for understanding tumor-supportive niches in FL pathogenesis.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"201-213"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles Improve Survival and Enhance Hematopoietic Recovery in Mice Exposed to High-Dose Irradiation.","authors":"Sicheng Wen, Mark Dooner, Mandy Pereira, Michael Del Tatto, Peter Quesenberry","doi":"10.1089/scd.2025.0036","DOIUrl":"10.1089/scd.2025.0036","url":null,"abstract":"<p><p>Exposure to high-dose radiation often results in hematopoietic acute radiation syndromes, leading to early mortality, while current therapies for patients exposed to lethal radiation doses are limited. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in tissue repair and regeneration but have not been well investigated for mitigating high-dose radiation damage. We previously demonstrated that human or murine MSC-EVs can reverse bone marrow injury caused by mild or moderate radiation. The current study evaluated the therapeutic potential of human MSC-EVs in mice exposed to high-dose total body irradiation (TBI). Mice were exposed to 0, 700, or 950 cGy TBI and subsequently received daily intravenous MSC-EV injections (1 × 10⁹ particles) for 3 days postirradiation. We evaluated survival rates, peripheral blood recovery, bone marrow engraftment, and bone marrow gene expression profiles at various intervals following treatment. MSC-EV administration significantly enhanced survival, with 70% of treated mice surviving 120 days after 950 cGy TBI exposure, compared with 0% survival in untreated controls by day 30. Although early peripheral blood recovery was not observed within 14 days, MSC-EV treatment facilitated substantial recovery at 3 months postirradiation, with significant increases in red blood cell, platelet, white blood cell, and hemoglobin levels, despite white blood cell and hemoglobin levels remaining slightly below normal. Furthermore, the engraftment capacity of bone marrow stem cells was significantly improved. The changes in hematopoietic-related gene expression presented at 14 days postirradiation returned to normal levels by 120 days in MSC-EV-treated mice. These results highlight the potential of MSC-EVs as a therapeutic strategy for high-dose radiation injuries by promoting hematopoietic recovery and improving survival. Our future research will focus on elucidating the radioprotective mechanisms and investigating their integration with existing therapies.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"189-200"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Complex I Inhibition on the Architecture of Neural Rosettes Differentiated from Human-Induced Pluripotent Stem Cells.","authors":"Stephanie Santarriaga, Magdalena Vater, Petra Dujmic, Kaia Gerlovin, Chun Wing Lee, Rakesh Karmacharya","doi":"10.1089/scd.2024.0169","DOIUrl":"10.1089/scd.2024.0169","url":null,"abstract":"<p><p>Orchestrated changes in cell arrangements and cell-to-cell contacts are susceptible to cellular stressors during central nervous system development. Effects of mitochondrial complex I inhibition on cell-to-cell contacts have been studied in vascular and intestinal structures; however, its effects on developing neuronal cells are largely unknown. We investigated the effects of the classical mitochondrial stressor and complex I inhibitor, rotenone, on the architecture of neural rosettes-radially organized neuronal progenitor cells (NPCs)-differentiated from human-induced pluripotent stem cells. We then analyzed the effects of rotenone on the distribution of cell-contact proteins within neural rosettes. Exposure to rotenone for 24 hours led to a dose-dependent irreversible disruption of the neural rosette architecture and relocalization of the cell-contact proteins ZO-1, β-catenin, and N-cadherin from the rosette center to the pericellular region. Though the levels of nestin and SOX2 remained unchanged, NPCs showed decreased levels of the NPC marker PAX6 and exhibited impaired neurogenesis following rotenone exposure. Our study suggests that complex I inhibition leads to a rearrangement of intercellular contacts with disruptive effects on neuronal development.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"164-176"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective Effects of Heme Oxygenase-1 Expression in Patients and Mice with Acute Graft-Versus-Host Disease?","authors":"Myrddin W Verheij, Ingrid Bulder, Mark Hoogenboezem, Ji-Ying Song, Mette D Hazenberg, Sacha S Zeerleder, Carlijn Voermans","doi":"10.1089/scd.2025.0013","DOIUrl":"10.1089/scd.2025.0013","url":null,"abstract":"<p><p>The development of acute graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is facilitated by damage-associated molecular patterns (DAMPs) released upon tissue damage due to the conditioning regimen. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme responsible for the breakdown of the DAMP cell-free heme. HO-1 plays a protective role in diseases characterized by systemic inflammation such as sepsis, but its role in the development of acute GvHD remains unclear. Here, we characterized the expression of HO-1 in a small cohort of allo-HSCT recipients with and without acute GvHD. We found HO-1 protein levels in plasma to be elevated in patients just before their acute GvHD diagnosis compared with baseline. Furthermore, HO-1 mRNA expression was increased in patients with acute GvHD at 1 and 3 months after allogeneic HSCT compared with patients without acute GvHD. Finally, induction of HO-1 in a humanized mouse model for acute GvHD led to lower disease scores and a reduction in weight loss. Overall, our data indicate that HO-1 expression is increased in patients with acute GvHD and that HO-1 induction might be able to provide protection against the disease, warranting further research into HO-1 as a target for clinical application.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"177-185"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptomeningeal Neural Organoid Fusions as Models to Study Meninges-Brain Signaling.","authors":"Hannah E Jones, Gabriella L Robertson, Caroline Bodnya, Alejandra Romero-Morales, Rebecca O'Rourke, Vivian Gama, Julie A Siegenthaler","doi":"10.1089/scd.2024.0231","DOIUrl":"10.1089/scd.2024.0231","url":null,"abstract":"<p><p>Neural organoids derived from human-induced pluripotent stem cells (iPSCs) provide a model to study the earliest stages of human brain development, including neurogenesis, neural differentiation, and synaptogenesis. However, neural organoids lack supportive tissues and some non-neural cell types that are key regulators of brain development. Neural organoids have instead been cocultured with non-neural structures and cell types to promote their maturation and model interactions with neuronal cells. One component of the brain that does not form de novo in neural organoids is the meninges, a trilayered structure that surrounds the central nervous system and secretes key signaling molecules required for mammalian brain development. Most studies of meninges-brain signaling have been performed in mice or using two-dimensional cultures of human cells, which do not accurately recapitulate the architecture and cellular diversity of the tissue. To overcome this, we developed a coculture system of neural organoids generated from human iPSCs fused with fetal leptomeninges (LPM) from mice with fluorescently labeled meninges (Col1a1-GFP), which we call leptomeningeal neural organoid (LMNO) fusions. This proof-of-concept study tests the stability of the different cell types in the LPM (fibroblasts and macrophages) and the fused neural organoid (progenitors and neurons), as well as the interface between the organoid and meningeal tissue. We test the longevity of the fusion pieces after 30 and 60 days in culture, describe best practices for preparing the meninges sample before fusion, and examine the feasibility of single or multiple meninges pieces fused to a single organoid. We discuss potential uses of the current version of the LMNO fusion model and opportunities to improve the system.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"152-163"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dark Clouds Looming Over Regenerative Medicine in Japan.","authors":"Hiroshi Kawaguchi","doi":"10.1089/scd.2025.0012","DOIUrl":"10.1089/scd.2025.0012","url":null,"abstract":"<p><p>Japan's regenerative medicine sector has encountered major challenges, underscored by the recent failures of products such as HeartSheet and Collategene. These setbacks expose critical weaknesses in the fast-track approval system, raising concerns about patient safety and the scientific robustness of product evaluations. Despite strong governmental support, addressing these fundamental issues is essential for the future success of regenerative medicine in Japan.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"149-151"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Neurotrophins in the Generation of Spiral Ganglion Neuron-Like Cells from Embryonic Stem Cells.","authors":"Anika Tabassum, Meng Deng, Zhengqing Hu","doi":"10.1089/scd.2024.0164","DOIUrl":"10.1089/scd.2024.0164","url":null,"abstract":"<p><p>Spiral ganglion neurons (SGNs) are crucial for transferring auditory signals from cochlear sensory hair cells to the brainstem. However, SGNs are usually damaged in sensorineural hearing loss. Embryonic stem cells (ESCs) have been used to regenerate SGNs, but it is obscure whether ESC-derived neurons can fully resemble SGN subtype features. This study aimed to understand the effect of neurotrophins on the generation of SGN-like cells from ESCs and their subsequent subtype specification. This study utilized a stepwise neuronal generation approach to direct DsRed ESCs toward neural progenitors and eventually SGN-like cells. The derived SGN-like cells expressed multiple neuronal markers, including Tuj1, Map2, and NeuN, indicating maturity. Neurotrophins, including brain-derived neurotrophic factor, neutrotrophin-3, and nerve growth factor, seemed to regulate the generation of mature neurons from ESCs. In addition, derived neuron-like cells expressed the otic protein marker Gata3 and glutamatergic marker VGluT1, suggesting that they are SGN-like the glutamatergic cells. Significantly more SGN subtype marker-positive cells, including Pou4f1, calbindin, and calretinin-positive cells, were observed in the neurotrophin treatment groups. Overall, this study indicates the potential of SGN subtype generation from ESCs, which could be significant for cochlear implant therapy or stem cell-based replacement studies.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"127-135"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}