Stem Cell Research & Therapy最新文献

{"title":"Mesenchymal stem cells derived from hPSC via neural crest attenuate chemotherapy-induced premature ovarian insufficiency by ameliorating apoptosis and oxidative stress in granulosa cells.","authors":"Xinran Li, Jinrong Liao, Youhong Zheng, Wei Cai, Jie Chen, Yu Liang, Yuanmei Chen, Xiaoxuan Li, Jiamao Luo, Jiaxin Xie, Manping Zhou, Lilin Hang, Xiujuan Sun, Xin Yue, Xuefeng Wang, Yifeng Wang, Huiyan Wang","doi":"10.1186/s13287-025-04346-x","DOIUrl":"10.1186/s13287-025-04346-x","url":null,"abstract":"<p><strong>Background: </strong>Premature ovarian insufficiency (POI) poses a significant threat to female reproductive health and currently lacks effective interventions. Recent studies highlight the promising potential of human pluripotent stem cell-derived mesenchymal stem cells (hPSC-MSC) in regenerative medicine. However, research on hPSC-MSC-based treatments for POI remains limited, particularly in the characterization of the intermediate differentiation stages from hPSC to MSC. This study presents an accelerated differentiation protocol for generating hPSC-MSC via neural crest cells (NCC) and evaluates their therapeutic potential in chemotherapy-induced POI.</p><p><strong>Methods: </strong>We modified a canonical small molecule-mediated protocol for hPSC-NCC-MSC differentiation. Systematic characterization of differentiated-cells was performed using qPCR, immunofluorescence, cell viability assays, flow cytometry and trilineage differentiation. In vivo, hPSC-NCC-MSC were transplanted into chemotherapy-induced POI SD rat models, and parameters such as body weight, ovarian weight, estrous cycle, hormone levels, follicle count, and mating were assessed. Granulosa cells (GC) apoptosis was analyzed using TUNEL assay and immunohistochemistry. In vitro, their effects on apoptosis inhibition and oxidative stress alleviation were investigated in a cultured GC cell line. Additionally, comparisons between umbilical cord MSC (UC-MSC) and hPSC-NCC-MSC in chemotherapy-induced POI was conducted.</p><p><strong>Results: </strong>Our optimized protocol, combining CHIR99021 and SB431542, efficiently induced NCC from both human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC). The programmed hPSC-NCC-MSC, characterized by specific NCC markers (P75, HNK1, SOX10, and AP2α), exhibited typical MSC morphology, trilineage differentiation potential, favorable cell viability, and prominent anti-senescence properties. Among these, NCC differentiated from H1-hESCs (H1-NCC) demonstrated the highest induction efficiency (72.45%), and H1-NCC-derived MSC (H1-NCC-MSC) displayed superior proliferation and anti-senescence properties compared to UC-MSC. Besides, H1-NCC-MSC exhibited therapeutic efficacy comparable to UC-MSC in both in vivo and in vitro models of chemotherapy-induced POI, potentially through mechanisms involving reduced GC apoptosis, alleviated oxidative stress, and improved mitochondrial function.</p><p><strong>Conclusions: </strong>Our findings propose a modified hPSC-NCC-MSC differentiation protocol, offering an inexhaustible and stable source for regenerative therapies. Furthermore, we provide the first experimental evidence that hPSC-NCC-MSC have therapeutic potential comparable to UC-MSC in restoring chemotherapy-induced POI. The underlying mechanisms are likely associated with paracrine-mediated effects on GC apoptosis, oxidative stress, and mitochondrial dysfunction.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"239"},"PeriodicalIF":7.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000327","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":"Human dental pulp stem cells attenuate airway inflammation in mice with PM_2.5-induced asthma exacerbation by inhibiting the pyroptosis pathway.","authors":"Jianling Liu, Yuehua Chen, Zhongpeng Li, Zhangwen Li, Fengjuan Lyu, Fang Wang, Aili Wang, Zhangquan Liu, Xiaoyang Liao, Jian Wu","doi":"10.1186/s13287-025-04368-5","DOIUrl":"10.1186/s13287-025-04368-5","url":null,"abstract":"<p><strong>Background: </strong>Fine particulate matter (PM_2.5) exposure significantly exacerbates respiratory morbidity, particularly in asthmatic individuals, highlighting an urgent need for effective therapeutic interventions. In this study, we evaluated the therapeutic potential and underlying mechanisms of human dental pulp stem cells (hDPSCs), a promising mesenchymal stem cell population, in mitigating airway inflammation in mice with PM_2.5-induced asthma exacerbation.</p><p><strong>Methods: </strong>In a PM_2.5-exacerbated ovalbumin (OVA)-asthma murine model, hDPSCs were intravenously administered with MCC950 (NLRP3 inhibitor) as positive control, systematically evaluating their therapeutic effects on airway inflammation and pyroptosis through pulmonary function tests, histopathological examination, cytological and molecular analyses.</p><p><strong>Results: </strong>The administration of hDPSCs ameliorated airway inflammation. Moreover, hDPSCs further alleviated Th2 inflammation and decreased serum IgE concentrations, along with a decrease in eosinophils in BALF. At the same time, interleukin-1β (IL-1β) and IL-18 levels in BALF and caspase-1 activity in lung tissues were reduced. In addition, immunohistochemistry showed that the expression levels of NLRP3, caspase-1, GSDMD, cleaved capsase-1 and IL-1β were reduced. The western blot results also showed that the expression level of NLRP3/caspase-1/GSDMD/cleaved capsase-1 in the classical pathway of pyroptosis decreased after hDPSCs intervention.</p><p><strong>Conclusions: </strong>These findings provided the first evidence that hDPSCs transplantation attenuated allergic airway inflammation and mucus secretion in mice with PM_2.5-induced asthma exacerbation. Thus, hDPSCs exert these protective effects through suppression of the NLRP3/caspase-1/GSDMD-mediated pyroptosis pathway, suggesting their potential as a novel cell-based therapy for PM_2.5 inhalation-mediated asthma.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"240"},"PeriodicalIF":7.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052630","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":"Challenges and opportunities in the compassionate use of out-of-specification products in autologous regenerative medicine.","authors":"Masao Sasai, Yayoi Kitawaki, Akihiro Umezawa, Yoshinori Oie, Takahiro Kamiya, Takuji Kawamura, Yoji Sato, Satoshi Hosoya, Hiroyuki Sugawara, Kazuto Yamada, Hiroshi Izumoto, Yoshiyuki Mae, Tohru Kuroda, Kiyoshi Okada","doi":"10.1186/s13287-025-04343-0","DOIUrl":"10.1186/s13287-025-04343-0","url":null,"abstract":"<p><strong>Background: </strong>In recent years, therapeutic preparations using patient-derived tissues have emerged as commercially approved regenerative medicine products for expanding treatment possibilities for patients with no other treatment options. Autologous cell-processed products, derived from the tissue of the patient, typically exhibit variability in raw material quality, resulting in the generation of out-of-specification (OOS) products.</p><p><strong>Main body: </strong>The compassionate use of OOS products is also practiced by the Food and Drug Administration and European Medicines Agency; differences among the three regulatory authorities were investigated to identify challenges in Japan. For conditions with no alternative treatments and severe time constraints, OOS products are sometimes used under compassionate grounds, particularly in Japan, where they are administered within the framework of clinical trials. This approach, although ethical, imposes significant operational and administrative burdens on medical institutions and marketing authorisation holders, raising concerns about sustainability. We considered the rationalisation of the current system and reached the conclusion that it would not contribute to load reduction and sustainability; thus, we devised a new framework.</p><p><strong>Conclusion: </strong>This study reviewed the compassionate use systems for OOS products in Japan, the United States, and Europe, highlighting current challenges and proposing a sustainable regulatory framework for future practice.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"238"},"PeriodicalIF":7.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044513","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":"Terpenes: natural compounds found in plants as potential senotherapeutics targeting senescent mesenchymal stromal cells and promoting apoptosis.","authors":"Valeria Mazzone, Nicola Alessio, Domenico Aprile, Giovanni Galano, Roberto De Rosa, Chiara Schiraldi, Giovanni Di Bernardo, Umberto Galderisi","doi":"10.1186/s13287-025-04310-9","DOIUrl":"https://doi.org/10.1186/s13287-025-04310-9","url":null,"abstract":"<p><strong>Background: </strong>Senescence in stem cells and progenitor cells can be particularly detrimental because these cells are essential for tissue renewal and overall organismal homeostasis. In mesenchymal stromal cells (MSCs), which comprise a heterogeneous mix of stem cells, progenitors, fibroblasts, and other stromal cells, senescence poses a significant challenge, as it impairs their ability to support tissue repair and maintenance. This decline in regenerative capacity can contribute to aging-related diseases, impaired wound healing, and degenerative disorders. One hallmark of senescence is resistance to apoptosis, mediated by activation of anti-apoptotic pathways. Consequently, senotherapeutics have emerged as a promising strategy to selectively eliminate senescent cells and promote healthy aging. Plant secondary metabolites, notably polyphenols and terpenes, exhibit diverse effects on living organisms and have served as medicinal agents.</p><p><strong>Methods: </strong>In this study, we investigated four terpenes-carvacrol, thymol, eugenol, and lycopene-for their senolytic potential in human senescent MSCs.</p><p><strong>Results: </strong>We found that these compounds induce apoptosis through both caspase-dependent and caspase-independent mechanisms, involving the activation of BAX, cytochrome c release, and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei. Importantly, terpene-induced apoptosis was associated with a significant increase in reactive oxygen species, and pre-incubation with glutathione partially rescued cell viability, confirming oxidative stress as a central trigger. Moreover, we identified SRC pathway modulation as a critical determinant of the senescence-to-apoptosis shift, highlighting a key regulatory switch in terpene action.</p><p><strong>Conclusions: </strong>These findings provide a detailed mechanistic dissection of terpene-induced senolysis and underscore their potential as promising candidates for senotherapeutics targeting senescent cells.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"231"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023776","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":"Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson's disease.","authors":"Bérengère Ballion, Marie-Laure Bonnet, Sébastien Brot, Afsaneh Gaillard","doi":"10.1186/s13287-025-04344-z","DOIUrl":"https://doi.org/10.1186/s13287-025-04344-z","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a complex neurological disorder characterized by the progressive degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). This degeneration disrupts the basal ganglia loops, leading to both motor and non-motor dysfunctions. Cell therapy for PD aims to replace lost mDA neurons to restore the DA neurotransmission in the denervated forebrain targets. In clinical trials for PD, mDA neurons are implanted into the target area, the striatum, and not in the SN where they are normally located. This ectopic localisation of cells may affect the functionality of transplanted neurons due to the absence of appropriate host afferent regulation. We recently demonstrated that human induced pluripotent stem cells (hiPSCs) derived mDA progenitors grafted into the substantia nigra pars compacta (SNpc) in a mouse model of PD, differentiated into mature mDA neurons, restored the degenerated nigrostriatal pathway, and induced motor recovery. The objective of the present study was to evaluate the long-term functionality of these intranigral-grafted mDA neurons by assessing their electrophysiological properties.</p><p><strong>Methods: </strong>We performed intranigral transplantation of hiPSC-derived mDA progenitors in a 6-hydroxydopamine RAG2-KO mouse model of PD. We recorded in vivo unit extracellular activity of grafted mDA neurons in anesthetised mice from 9 to 12 months post-transplantation. Their electrophysiological properties, including firing rates, patterns and spike characteristics, were analysed and compared with those of native nigral dopaminergic neurons from control mice.</p><p><strong>Results: </strong>We demonstrated that these grafted mDA neurons exhibited functional characteristics similar to those of native nigral dopaminergic neurons, such as large bi- or triphasic spike waveforms, low firing rates, pacemaker-like properties, and two single-spike firing patterns. Although grafted mDA neurons also displayed low discharge frequencies below 10 Hz, their mean frequency was significantly lower than that of nigral mDA neurons, with a differential pattern distribution.</p><p><strong>Conclusions: </strong>Our findings indicate that grafted mDA neurons exhibit dopaminergic-like functional properties, including intrinsic membrane potential oscillations leading to regular firing patterns. Additionally, they demonstrated irregular and burst firing patterns, suggesting they receive modulatory inputs. However, grafted mDA neurons displayed distinct properties, potentially related to their human origin or the incomplete maturation one year after transplantation.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"232"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000111","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":"Human umbilical cord mesenchymal stem cell-derived exosomes repair IBD by activating the SIRT1-FXR pathway in macrophages.","authors":"Mengjiao Zhou, Bing Pei, Peipei Cai, Chengxue Yi, Francis Atim Akanyibah, Changkun Lyu, Fei Mao","doi":"10.1186/s13287-025-04365-8","DOIUrl":"https://doi.org/10.1186/s13287-025-04365-8","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory bowel disease (IBD), a chronic immune disorder, has increasing global incidence and poor treatment outcome. Abnormal macrophage function is implicated in the pathophysiology of IBD. In this study, we investigated the mechanism by which human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) inhibit inflammation in IBD mouse and macrophage inflammation models.</p><p><strong>Methods: </strong>We established a dextran sodium sulfate (DSS)-induce BALB/c mice model of IBD and treated with hucMSC-Ex via tail vein to evaluate their repair effect on IBD mice. An in vitro macrophage inflammation model was established using lipopolysaccharide (LPS) and Nigericin (Nig) by stimulating mouse macrophage RAW264.7 and human myeloid leukemia mononuclear (THP-1) cells to assess the repair effect of hucMSC-Ex on macrophage inflammation. EX 527, an effective inhibitor of silent information regulator of transcription 1 (SIRT1), was employed in both the in vivo and in vitro models to explore the effect of hucMSC-Ex on the SIRT1-FXR (farnesoid X receptor) pathway in macrophages during the attenuation of inflammation.</p><p><strong>Results: </strong>HucMSC-Ex effectively inhibited inflammation in both the in vivo and in vitro models by up-regulating the expressions of SIRT1 and FXR, which reduced the acetylation level of FXR and inhibited the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. The addition of EX 527 further proved that hucMSC-Ex can reduce the acetylation of FXR by activating the SIRT1-FXR pathway, and the decrease of FXR acetylation was directly related to the inhibition of the activity of the NLRP3 inflammasome.</p><p><strong>Conclusion: </strong>HucMSC-Ex alleviates IBD by reducing the acetylation level of FXR through activating the SIRT1-FXR pathway in macrophages and directly negatively regulating the activation of NLRP3 inflammasomes, thus inhibiting the occurrence of the inflammatory process.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"233"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987850","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":"Functional analysis of JPH2-knockout cardiomyocytes identifies ECCD as a novel indicator in a human cardiac modelJPH2.","authors":"Tianwei Guo, Hongyue Wang, Fujian Wu, Wenjing Lu, Min Zhu, Shuhong Ma, Yongshuai Zhang, Yuting Yan, Meng Zhou, Didaer Talanaite, Siyu Liu, Man Qi, Feng Lan, Xujie Liu","doi":"10.1186/s13287-025-04323-4","DOIUrl":"https://doi.org/10.1186/s13287-025-04323-4","url":null,"abstract":"<p><strong>Background: </strong>Junctophilin-2 (JPH2) is a vital protein in cardiomyocytes, anchoring T-tubule and sarcoplasmic reticulum membranes to facilitate excitation-contraction coupling, a process essential for cardiac contractile function. Dysfunction of JPH2 is associated with cardiac disorders such as heart failure; however, prior studies using mouse models or primary human cardiomyocytes are limited by interspecies differences or poor cell viability, respectively. This study aimed to investigate JPH2's role in human cardiac function and disease using a novel stem cell-derived model, while introducing a new indicator to evaluate related cardiac impairments.</p><p><strong>Methods: </strong>We generated a JPH2-knockout model using human embryonic stem cell-derived cardiomyocytes (hESC-CMs) with CRISPR/Cas9. Cellular morphology, contractile function, calcium dynamics, and electrophysiological properties were assessed via transmission electron microscopy, the CardioExcyte96 system, calcium imaging with Fluo-4 AM, and multi-electrode array recordings, respectively. Wild-type JPH2 was overexpressed through lentiviral transfection to evaluate rescue effects, and two JPH2 variants-one benign (G505S) and one pathogenic (E85K)-were introduced to study mutation-specific effects.</p><p><strong>Results: </strong>JPH2 knockout disrupted excitation-contraction coupling in hESC-CMs by impairing junctional membrane complex structure, leading to heart failure-like phenotypes with reduced contractility, altered calcium dynamics, and electrophysiological irregularities. Overexpression of wild-type JPH2 restored these functions, affirming its critical role in cardiac physiology. We identified excitation-contraction coupling delay (ECCD) as a novel indicator that precisely quantified coupling impairment severity, with its applicability validated across distinct JPH2 variants (G505S and E85K).</p><p><strong>Conclusions: </strong>This study demonstrates JPH2's essential role in sustaining excitation-contraction coupling by stabilizing the junctional membrane complex, with its deficiency driving heart failure-like cardiac dysfunction. ECCD is established as a sensitive, comprehensive indicator for assessing JPH2-related impairment severity. These findings advance our understanding of JPH2 in cardiac pathology and position ECCD as a valuable tool for research and potential clinical evaluation, with JPH2 and calcium regulation emerging as promising therapeutic targets.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"234"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049458","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":"Subchondral injection of human umbilical cord mesenchymal stem cells ameliorates knee osteoarthritis by inhibiting osteoblast apoptosis and TGF-beta activity.","authors":"Congzi Wu, HuiHui Xu, Zhen Wu, Haipeng Huang, Qinwen Ge, Jianbo Xu, Jiali Chen, Pinger Wang, Wenhua Yuan, Hongting Jin, Peijian Tong","doi":"10.1186/s13287-025-04366-7","DOIUrl":"https://doi.org/10.1186/s13287-025-04366-7","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a common degenerative disease caused by multiple pathological mechanisms wherein subchondral bone malfunction plays a substantial role. Recently, subchondral (SC) injection of orthobiologics has been attracting growing interest albeit the mainstream delivery method of mesenchymal stem cells (MSCs) is through intra-articular (IA). This study investigates the effect of SC injection of human umbilical cord mesenchymal stem cells (UCMSCs) on OA and its possible therapeutic mechanism compared to IA injection.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) received saline or UCMSC injections via SC or IA. Consecutive injections once a week for three weeks and withdrawal for another four weeks, followed by Radiographical scanning, histopathological, immunohistochemical, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining. Cell counting Kit-8 (CCK-8) assay, alkaline phosphatase (ALP), alizarin red staining (ARS), TUNEL, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed in TNFα-induced MC3T3-E1 cells to illustrate the exact pathogenesis mechanism.</p><p><strong>Results: </strong>IA and SC UCMSC injections preserved cartilage, synovium, and subchondral bone parameters like trabecular bone volume fraction (BV/TV). SC injection uniquely improved Trabecular separation (Tb.Sp) and Trabecular number (Tb.N). SC and IA injections of UCMSCs demonstrated equivalent efficacy in promoting osteoblastic bone formation and attenuating aberrant angiogenesis of subchondral bone. In addition, we demonstrated that osteoblast apoptosis and Smad2-dependent TGF-beta (TGF-β) are crucial and interactive subchondral bone pathological features in OA. In vivo and vitro studies further revealed that UCMSCs inhibited excessive TGF-β/pSmad2 signaling to regulate aberrant vascularization, osteoblast apoptosis and differentiation imbalance, ultimately maintaining osteochondral homeostasis.</p><p><strong>Conclusions: </strong>The efficacy of UCMSCs for treating OA rats via SC injection was equivalent to that of IA; and even superior to IA in terms of subchondral bone phenotype via regulating apoptosis and TGF-β/pSmad2 signaling in osteoblasts, suggesting SC injection of UCMSCs as a potential and promising cell therapy for OA treatment.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"235"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014045","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":"Human menstrual blood-derived stem cells secreted ECM1 directly interacts with LRP1α to ameliorate hepatic fibrosis through FoxO1 and mTOR signaling pathway.","authors":"Yangxin Fang, Lin Chen, Yin Yuan, Sining Zhou, Jiamin Fu, Qi Zhang, Ning Zhang, Yuqi Huang, Yifei Li, Li Yuan, Lijun Chen, Charlie Xiang","doi":"10.1186/s13287-025-04351-0","DOIUrl":"https://doi.org/10.1186/s13287-025-04351-0","url":null,"abstract":"<p><strong>Background: </strong>Human menstrual blood-derived stem cells (MenSCs), a major class of mesenchymal stem cells (MSCs), modulate intercellular signals via paracrine factors. Previous studies found that MenSC-derived secretomes exert protective effects against liver fibrosis. However, the underlying mechanisms of these observations remain unclear.</p><p><strong>Methods: </strong>Extracellular Matrix Protein 1 (ECM1), identified in MenSCs culture medium using mass spectrometry, was employed to stably overexpress ECM1-HA or silence in MenSCs using lentiviral vectors. These genetically engineered cells were either intravenously injected into the carbon tetrachloride (CCl₄)-induced liver fibrosis mice or co-cultured with hepatic stellate cells (HSCs)-LX-2. The interaction between ECM1 and low-density lipoprotein receptor-related protein 1α (LRP1α) was confirmed using Co-Immunoprecipitation (Co-ip), Duolink Proximity Ligation Assays (PLA) and pull-down. LRP1 deficient mice were generated via intravenous administration of adeno-associated-virus-8. The downstream molecular mechanisms were characterized by non-target metabolomics and multiplex immunohistochemical staining. RNA sequencing was performed to evaluate the genetic alterations in various genes within the MenSCs.</p><p><strong>Results: </strong>MenSC-secreted ECM1 exhibits potential to ameliorate liver fibrosis by inactivating HSCs, improving liver functions, and reducing collagen deposition in both cellular and mouse model of the CCl₄-induced liver fibrosis. Mechanistically, a novel interaction was identified that ECM1 directly bound to cell surface receptor LRP1α. Notably, the antifibrotic efficacy of MenSC was negated in LRP1-deficient cells and mice. Moreover, the ECM1-LRP1 axis contributed to the alleviation of liver fibrosis by suppressing AKT/mTOR while activating the FoxO1 signaling pathway, thereby facilitating pyrimidine and purine metabolism. Additionally, ECM1-modified MenSCs regulate the transcription of intrinsic cytokine genes, further mitigating liver fibrosis.</p><p><strong>Conclusions: </strong>These findings highlight an extensive network of ECM1-LRP1 interaction, which serve as a link for providing promising insights into the mechanism of MenSC-based drug development for liver fibrosis. Our study also potentially presents novel avenues for clinical antifibrotic therapy.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"230"},"PeriodicalIF":7.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032188","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":"From bone marrow mesenchymal stem cells to diseases: the crucial role of m⁶A methylation in orthopedics.","authors":"Peng Li, Chu Zhang, Wen Yin, Mijia Tao, Zhipeng Niu, Yutao Cui, Dankai Wu, Feng Gao","doi":"10.1186/s13287-025-04364-9","DOIUrl":"https://doi.org/10.1186/s13287-025-04364-9","url":null,"abstract":"<p><p>Elucidating the molecular mechanisms underlying orthopedic diseases is crucial for guiding therapeutic strategies and developing innovative interventions. N6-methyladenosine (m⁶A)-an epitranscriptomic modification-has emerged as a key regulator of cellular fate and tissue homeostasis. Specifically, m⁶A plays a pivotal role in several RNA biological processes such as precursor RNA splicing, 3'-end processing, nuclear export, translation, and stability. Recent advancements indicate that m⁶A methylation regulates stem cell proliferation and osteogenic differentiation by modulating various signaling pathways. Extensive research has shown that abnormalities in m⁶A methylation contribute significantly to the onset and progression of various orthopedic diseases such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), and bone tumors. This review aims to summarize the key proteases involved in m⁶A methylation and their functions. The detailed mechanisms by which m⁶A methylation regulates osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through direct and indirect ways are also discussed, with a focus on specific molecular pathways. Finally, this review analyzes the roles and mechanisms of m⁶A modification in the development and progression of multiple orthopedic diseases, offering a comprehensive understanding of the pathophysiology of these conditions and proposing new directions and molecular targets for innovative treatment strategies.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"228"},"PeriodicalIF":7.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982012","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}