Yuzhou Gu, Lu Chen, Shuying Chen, Yuhao Wu, Shengjie Hao, Feiyin Sheng, Jiali Yuan, Zhenwei Qin, Di Wu, Yu Han, Zengying Yao, Zhijian Chen, I Michael Wormstone, Yibo Yu, Junbin Qian, Qiuli Fu, Ke Yao
{"title":"A single-cell transcriptomic atlas of human lens epithelium: identification and functional insights into lens stem/progenitor cells.","authors":"Yuzhou Gu, Lu Chen, Shuying Chen, Yuhao Wu, Shengjie Hao, Feiyin Sheng, Jiali Yuan, Zhenwei Qin, Di Wu, Yu Han, Zengying Yao, Zhijian Chen, I Michael Wormstone, Yibo Yu, Junbin Qian, Qiuli Fu, Ke Yao","doi":"10.1186/s13287-025-04436-w","DOIUrl":"10.1186/s13287-025-04436-w","url":null,"abstract":"<p><strong>Background: </strong>The existence of stem/progenitor cells in the lens epithelium has been demonstrated, but their identification remains challenging. Accurate identification requires advanced technologies and a comprehensive understanding of lens epithelial cell (LEC) subtypes, presenting a significant challenge in age-related cataract research.</p><p><strong>Methods: </strong>Eight pairs of human donor lens epithelium samples were collected for single-cell RNA sequencing (scRNA-seq). This included four non-aged (< 65 years) and four aged (> 65 years) individuals. Subsequent analyses involved cell (sub)type characterization, trajectory inference, and cell-cell communication. Experimental validation was conducted through transcriptome sequencing and immunofluorescence on human lenses, lens organoids, rabbit regenerated lenses, mouse lenses, and cell lines.</p><p><strong>Results: </strong>Six groups were identified via UMAP mapping of scRNA-seq data: four LECs, one lens fiber cells (LFCs), and one immune cells. One of the four LEC clusters exhibited a distinct gene expression profile and was identified as transient amplifying cells (TACs). TACs specifically express TOP2A and are localized at the lens equator. CytoTRACE analysis to the LEC and LFC data sets provided a differentiation trajectory. The TAC group was determined as stage 2 in the trajectory and LFCs last. The 3 sub groups were labelled early, mid and late LECs and corresponded to stage 1, 3 and 4 in the path. While cell population demographics remained stable with age, transcriptomic changes in LECs were observed, including weaker intercellular crosstalk and adhesion, and fewer TACs in S phase. Lens progenitor-like cells (LPLCs) were identified as a sub-population in early LECs and express ID1. In addition, pleiotrophin (PTN) signaling was prevalent at all differentiation stages, with a notable weakening of PTN signaling in aged LPLCs.</p><p><strong>Conclusions: </strong>This study identified four subclasses of LECs within the human lens epithelium that follow a progressive staged development pathway from progenitor cells to mature LECs. TOP2A can serve as a biomarker for TAC in the lens, and LPLCs sustain their dedifferentiated state by expressing ID1. The aging process does not appear to alter cell population demographics, but significant alteration in gene expression profile is observed. Moreover, PTN signaling emerges as a crucial factor in lens homeostasis and represents a potential target for cataract drug development.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"333"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544926","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}
Dawei Wang, Ao Chen, Yuan Fang, Chuanxue Ma, Yafei Lu, Chungen Zhou, Qizhi Liu, Bin Jiang
{"title":"Engineering strategies to enhance the research progress of mesenchymal stem cells in wound healing.","authors":"Dawei Wang, Ao Chen, Yuan Fang, Chuanxue Ma, Yafei Lu, Chungen Zhou, Qizhi Liu, Bin Jiang","doi":"10.1186/s13287-025-04471-7","DOIUrl":"10.1186/s13287-025-04471-7","url":null,"abstract":"","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"342"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544930","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}
Wen Xing, Fang Dong, Yining Liu, Jiajia Yuan, Chao Chen, Yihan Li, Han Wang, Ming Yao, Ting Chen, Tao Cheng, Sha Hao, Yuan Zhou
{"title":"Deletion of p18<sup>INK4c</sup> enhances both osteogenesis and hematopoietic supportive capacity of bone marrow mesenchymal stromal cells.","authors":"Wen Xing, Fang Dong, Yining Liu, Jiajia Yuan, Chao Chen, Yihan Li, Han Wang, Ming Yao, Ting Chen, Tao Cheng, Sha Hao, Yuan Zhou","doi":"10.1186/s13287-025-04402-6","DOIUrl":"10.1186/s13287-025-04402-6","url":null,"abstract":"<p><strong>Background: </strong>p18<sup>INK4 C</sup> (CDKN2C, encoded by p18<sup>INK4c</sup> or Cdkn2c) is an early G1-phase cyclin-dependent kinase inhibitor protein. Previous studies demonstrated enhanced self-renewal capacity of hematopoietic stem cells (HSCs) in p18<sup>-/-</sup> mice compared to wild-type (WT) mice. Given the critical role of bone marrow niche cells-particularly mesenchymal stromal cells (MSCs)-in hematopoiesis, this study investigated the functional alterations of p18<sup>-/-</sup> MSCs and their impact on hematopoietic support.</p><p><strong>Methods: </strong>Bone marrow derived MSCs were isolated from p18<sup>-/-</sup> and WT mice. Their proliferation and differentiation capacities were assessed, followed by evaluation of hematopoietic support using cobblestone area-forming cell assay and long-term culture-initiating cell assay. RNA sequencing was performed to analyze the transcriptional profile of p18<sup>-/-</sup> MSCs, with a focus on differentially expressed genes (DEGs). Key pathways associated with hematopoietic support were identified using Ingenuity Pathway Analysis. A candidate protein was quantified by ELISA, and its functional role in hematopoietic support was validated via a modified coculture system.</p><p><strong>Results: </strong>p18<sup>-/-</sup> MSCs displayed an increased proliferation rate, preferential differentiation toward osteogenesis over adipogenesis, and enhanced hematopoietic support. RNA sequencing analysis identified 137 DEGs, with secreted phosphoprotein 1 (Spp1, encoding osteopontin, Opn) being significantly upregulated in p18<sup>-/-</sup> MSCs. Elevated Opn levels were confirmed in both bone marrow and MSC-conditioned media from p18<sup>-/-</sup> mice. Functional validation further demonstrated that Opn enhanced the hematopoietic supportive capacity of MSCs in vitro.</p><p><strong>Conclusions: </strong>p18 deficiency promotes osteogenic differentiation and enhances the hematopoietic supportive function of MSCs, likely mediated by Opn upregulation. These findings suggest a potential therapeutic strategy for improving bone regeneration and HSC expansion.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"334"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544928","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":"Engineering biomimetic bone marrow niche with gene modified mesenchymal stromal cells for ex vivo culture of human hematopoietic stem and progenitor cells.","authors":"Sevanthy Suresh, Vigneshwaran Venkatesan, Manoj Kumar K Azhagiri, Gokulnath Mahalingam, Prathibha Babu Chandraprabha, Mohankumar K Murugesan, Sanjay Kumar, Saravanabhavan Thangavel, Srujan Marepally","doi":"10.1186/s13287-025-04474-4","DOIUrl":"10.1186/s13287-025-04474-4","url":null,"abstract":"<p><strong>Background: </strong>Hematopoietic Stem and Progenitor Cells (HSPCs) gene therapy has shown significant progress, with commercial approval for at least four distinct haematological disorders, and poised for a rapid expansion in the upcoming years. Despite these advancements, the ex vivo culture of HSPCs continues to present significant challenges. The stress induced by ex vivo culture can negatively impact transplantation outcomes, while the need for exogenous cytokine supplementation contributes to the high costs associated with gene therapy products.</p><p><strong>Methods: </strong>We developed genetically modified human bone marrow MSCs (GM-MSCs) secreting cytokines such as Stem cell factor (SCF), Thrombopoietin (TPO), FMS-like tyrosine kinase-3-ligand (FLT3L), and Interleukin-3 (IL3), closely resembling bone marrow cellular niche to augment HSPCs culture.</p><p><strong>Results: </strong>HSPCs proliferate on GM-MSCs akin to standard conditions, devoid of external cytokine supplementation and these HSPCs retain their stem cell characteristics, colony-forming potential, stemness gene signatures, and capacity for long-term multilineage reconstitution in NBSGW mice. We demonstrate that our biomimetic feeder layer supports and alleviates stress associated with Homology Directed Repair (HDR) mediated gene-editing of HSPCs for fetal haemoglobin reactivation for a potential application in β-hemoglobinopathies gene therapy.</p><p><strong>Conclusion: </strong>Our GM-MSCs offer a compelling alternative to traditional cytokine supplementation by establishing a biomimetic bone marrow niche that fosters HSPC expansion while maintaining their stemness. These findings underscore the potential of engineered MSCs to revolutionize ex vivo HSPCs culture, ultimately enhancing their therapeutic value for gene therapy applications.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"335"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544929","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}
Anna Pezzotta, Alessandra Bovio, Barbara Imberti, Monica Locatelli, Daniela Corna, Domenico Cerullo, Sara Gastoldi, Ariela Benigni, Giuseppe Remuzzi, Marina Morigi, Luca Perico
{"title":"Mesenchymal stromal cell secretome reduces lung injury and thrombo-inflammation induced by SARS-CoV-2 spike protein.","authors":"Anna Pezzotta, Alessandra Bovio, Barbara Imberti, Monica Locatelli, Daniela Corna, Domenico Cerullo, Sara Gastoldi, Ariela Benigni, Giuseppe Remuzzi, Marina Morigi, Luca Perico","doi":"10.1186/s13287-025-04472-6","DOIUrl":"10.1186/s13287-025-04472-6","url":null,"abstract":"<p><p>Severe COVID-19 is characterized by thrombo-inflammatory processes within the lung microvasculature. In pursuit of effective treatments, clinical studies explored mesenchymal stromal cells (MSCs) as a promising approach due to their anti-inflammatory, immunomodulatory, and regenerative properties, through their paracrine action.Here, we tested the conditioned medium (CM) derived from human umbilical cord (UC)-MSCs in acute lung injury induced by the spike protein subunit 1 (S1) in ACE2-humanized male mice. Injection of CM significantly limited S1-induced lung injury, edema, and fibrosis. This was associated with reduced vascular dysfunction, in terms of restored thrombomodulin levels and decreased von Willebrand (vWF) expression. By preserving endothelial glycocalyx, CM reduced complement C3 accumulation, favoring factor H binding on the lung microvasculature. Reduced oxidative stress, nuclear NF-κB p65 accumulation, and inflammatory cell infiltration were also observed in response to CM in S1-injected mice.In vitro, CM counteracted thrombo-inflammation by preserving thrombomodulin, as well as limiting vWF expression, due to endothelial glycocalyx recovery. CM reduced nuclear translocation of NF-κB p65 and its downstream targets, ICAM-1 and P-selectin, translating in decreased C3 deposits, platelet aggregation, and leukocyte adhesion on S1-challenged endothelial cells.Collectively, these data indicate that UC-MSC-derived secretome represents a promising therapy in COVID-19 due to its potent anti-thrombotic and anti-inflammatory effects on lung microcirculation.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"324"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544937","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 stromal vascular fraction mitigates bleomycin-induced skin fibrosis in mice by modulating vascular lesions and secreting antifibrotic factors at different stages of disease.","authors":"Ziyu Wang, Mengqi Shi, Zonghao Liu, Yahui Chen, Xiangguang Shi, Jiucun Wang","doi":"10.1186/s13287-025-04470-8","DOIUrl":"10.1186/s13287-025-04470-8","url":null,"abstract":"<p><strong>Background: </strong>Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs, leading to significant morbidity and reduced quality of life. Despite ongoing research, the underlying pathogenesis of SSc remains unclear, and treatment options are limited. Stromal vascular fraction (SVF), a naturally occurring cell population that includes mesenchymal stem cells (MSCs), has emerged as a potential therapeutic agent for various fibrotic diseases. This study aimed to investigate the therapeutic effects and underlying mechanisms of SVF in a bleomycin-induced mouse model of skin fibrosis.</p><p><strong>Methods: </strong>SVF was isolated from the inguinal adipose tissue of C57BL/6 mice and administered subcutaneously or intradermally at different disease stages to assess its impact on skin fibrosis. Histological analyses were performed to evaluate dermal thickness and collagen deposition. In vivo imaging and immunofluorescence were used to track the retention of SVF within fibrotic tissue over time, particularly in the subcutaneous layer. Flow cytometry and immunofluorescence were employed to examine cutaneous vascular pathology and the secretion of antifibrotic factors, such as hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF-2). Finally, we investigated the contribution of major SVF subsets to cutaneous fibrosis and the mechanisms by which these subsets mediate therapeutic effects.</p><p><strong>Results: </strong>SVF significantly attenuated skin fibrosis in both early and late stages of disease, as evidenced by reduced dermal thickness and collagen deposition. Notably, SVF showed prolonged retention in fibrotic tissues-especially in the subcutaneous layer-for at least 18 days post-injection, with antifibrotic effects primarily mediated through paracrine mechanisms. In early-stage fibrosis, SVF inhibited endothelial-mesenchymal transition and mitigated skin vascular damage. In late-stage fibrosis, SVF continued to secrete antifibrotic factors, including HGF and FGF-2. Subsequent analyses identified the CD45-negative subset of SVF as a key regulator of skin fibrosis.</p><p><strong>Conclusion: </strong>SVF, particularly its CD45-negative subset, holds considerable promise for the treatment of SSc-associated skin fibrosis. These findings suggest that SVF-based therapies could be effective in managing fibrosis-related diseases and offer valuable insights for future clinical applications.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"328"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544947","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":"Enhancing fat graft retention through adipose tissue browning: a systematic review.","authors":"He Qiu, Hang Wang, Qiang Ji, Dongmei Wu","doi":"10.1186/s13287-025-04473-5","DOIUrl":"10.1186/s13287-025-04473-5","url":null,"abstract":"<p><strong>Background: </strong>Recently, existing researches have gradually recognized the critical biological behaviour played by spontaneous or exogenous-induced browning conversion in fat transplantation. However, no comprehensive review explored the fat grafts remodeling process toward browning and such role in fat graft retention.</p><p><strong>Aims: </strong>This study aimed to elucidate the behavioral characteristics of browning changes following fat grafting, as well as its benefits and mechanisms on the survival of transplanted fat.</p><p><strong>Methods: </strong>Databases including Web of science, PubMed, Ovid medline, and Embase were searched from inception through September 2024. Studies related to fat grafts browning in fat transplantation were systematically reviewed, in accordance with the inclusion and exclusion criteria.</p><p><strong>Results: </strong>We evaluated 14 studies including 13 animal works and one clinical report. Five studies directly transplanted fat without any browning induction, while others utilized either beige fat or pre-treated grafts with browning stimuli.Data shown that around the periphery of fat grafts (predominantly in survival zone), early accumulations of graft browning can be observed, dynamically accompanying the stable remodeling of the graft. Post-transplantation spontaneous browning typically begins around day 7, stabilizes after approximately 3 months, and may revert to white adipose tissue. The favorable browning up-regulation behavior of fat graft can enhance graft retention by promoting early angiogenesis, reducing inflammation, and upregulating adipogenesis. The origin of beige adipocytes, whether from the conversion of white adipocytes or the regeneration of progenitor cells, remains underdiscussed.</p><p><strong>Conclusions: </strong>Notwithstanding the relatively limited sample and study levels, this work offers valuable insights into the benefits of browning behavior on enhancing fat graft retention. The in-depth understanding of the underlying mechanism of browning and manipulating its switching in fat grafting will contribute in several ways to achieving desired clinical outcomes.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"344"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544931","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}
Narges Maleki, Maryam Rezapour Kalkhorann, Mohammad Sajad Sajad Emami Aleagha, Amir Emami, Abdolamir Allameh
{"title":"MSCs engineered with secreted Klotho alleviate blood-brain barrier disruption and reduce neuroinflammation more effectively than MSCs in experimental autoimmune encephalomyelitis.","authors":"Narges Maleki, Maryam Rezapour Kalkhorann, Mohammad Sajad Sajad Emami Aleagha, Amir Emami, Abdolamir Allameh","doi":"10.1186/s13287-025-04428-w","DOIUrl":"10.1186/s13287-025-04428-w","url":null,"abstract":"<p><strong>Background: </strong>The anti-aging protein, Klotho, has been shown to exert neuroprotective effects in neurodegenerative disorders. This study was designed to evaluate the effects of MSCs engineered with secreted Klotho (SKL-MSCs) on neuroinflammation in experimental autoimmune encephalomyelitis (EAE) mouse model and to investigate underlying molecular mechanisms.</p><p><strong>Methods: </strong>EAE was induced in female C57BL/6 mice, and animals were then randomized to receive PBS, MSCs, or SKL-MSCs at the onset of disease. BBB permeability assay was performed. The mRNA and protein expression of inflammatory factors was detected in the brain of animals by real-time PCR and immunohistochemistry, respectively. The mRNA and protein expression of BBB-associated factors was detected in the brain of animals by real-time PCR and Western blotting, respectively.</p><p><strong>Results: </strong>The results showed that SKL-MSCs slowed EAE progression and attenuated the disease severity more effectively than MSCs. SKL-MSCs also decreased the expression of TNF-α, IFN-γ, and IL-17 but increased the expression of IL-10 more potently than MSCs in the brain of EAE animals. Furthermore, SKL-MSCs reduced BBB permeability more significantly than MSCs, which was accompanied by decreased levels of BBB-associated factors, ICAM-1, VCAM-1, MMP-9, and CCL2, in the brain of EAE animals. However, in mice treated with MSCs, the reduction in the expression of BBB-associated factors was limited to ICAM-1 and MMP-9.</p><p><strong>Conclusions: </strong>Our study highlighted the significantly greater therapeutic power of SKL-MSCs compared with MSCs in attenuating EAE disease severity and reducing neuroinflammation, which might be mediated through a more marked reduction in the BBB permeability and BBB-associated factors expression levels in the brain of animals.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"346"},"PeriodicalIF":7.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544939","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}