Stem Cell Research & Therapy最新文献

{"title":"RNA-binding protein SAMD4A targets FGF2 to regulate cardiomyocyte lineage specification from human embryonic stem cells.","authors":"Na Yi, Han-Rui Wang, Yu-Ping Zhu, Tao Xiao, Qin Lin, Huan Liu, Yi-Lei Meng, Yi-Zhuo Sun, Fang Lin, Sang-Yu Hu, Hua-Ming Cao, Jun-Fang Zhang, Lu-Ying Peng, Li Li","doi":"10.1186/s13287-025-04269-7","DOIUrl":"10.1186/s13287-025-04269-7","url":null,"abstract":"<p><strong>Background: </strong>RNA-binding proteins (RBPs) are essential in cardiac development. However, a large of them have not been characterized during the process.</p><p><strong>Methods: </strong>We applied the human embryonic stem cells (hESCs) differentiated into cardiomyocytes model and constructed SAMD4A-knockdown/overexpression hESCs to investigate the role of SAMD4A in cardiomyocyte lineage specification.</p><p><strong>Results: </strong>SAMD4A, an RBP, exhibits increased expression during early heart development. Suppression of SAMD4A inhibits the proliferation of hESCs, impedes cardiac mesoderm differentiation, and impairs the function of hESC-derived cardiomyocytes. Correspondingly, forced expression of SAMD4A enhances proliferation and promotes cardiomyogenesis. Mechanistically, SAMD4A specifically binds to FGF2 via a specific CNGG/CNGGN motif, stabilizing its mRNA and enhancing translation, thereby upregulating FGF2 expression, which subsequently modulates the AKT signaling pathway and regulates cardiomyocyte lineage differentiation. Additionally, supplementation of FGF2 can rescue the proliferation defect of hESCs in the absence of SAMD4A.</p><p><strong>Conclusions: </strong>Our study demonstrates that SAMD4A orchestrates cardiomyocyte lineage commitment through the post-transcriptional regulation of FGF2 and modulation of AKT signaling. These findings not only underscore the essential role of SAMD4A in cardiac organogenesis, but also provide critical insights into the molecular mechanisms underlying heart development, thereby informing potential therapeutic strategies for congenital heart disease.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"144"},"PeriodicalIF":7.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658704","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 establishment and regulation of human germ cell lineage.","authors":"Honglin Yu, Ziqi Wang, Jiayue Ma, Ruoming Wang, Shuo Yao, Zhaoyu Gu, Kexin Lin, Jinlan Li, Robert S Young, Ya Yu, You Yu, Min Jin, Di Chen","doi":"10.1186/s13287-025-04171-2","DOIUrl":"10.1186/s13287-025-04171-2","url":null,"abstract":"<p><p>The specification of primordial germ cells (PGCs) during early embryogenesis initiates the development of the germ cell lineage that ensures the perpetuation of genetic and epigenetic information from parents to offspring. Defects in germ cell development may lead to infertility or birth defects. Historically, our understanding of human PGCs (hPGCs) regulation has primarily been derived from studies in mice, given the ethical restrictions and practical limitations of human embryos at the stage of PGC specification. However, recent studies have increasingly highlighted significant mechanistic differences for PGC development in humans and mice. The past decade has witnessed the establishment of human pluripotent stem cell (hPSC)-derived hPGC-like cells (hPGCLCs) as new models for studying hPGC fate specification and differentiation. In this review, we systematically summarize the current hPSC-derived models for hPGCLC induction, and how these studies uncover the regulatory machinery for human germ cell fate specification and differentiation, forming the basis for reconstituting gametogenesis in vitro from hPSCs for clinical applications and disease modeling.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"139"},"PeriodicalIF":7.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658707","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":"Exploring the impact of gut microbiota-mediated regulation of exosomal miRNAs from bone marrow mesenchymal stem cells on the regulation of bone metabolism.","authors":"Bin He, Xianglin Shen, Feng Li, Rudan Zhou, Haiyan Xue, Xianqiu Fan, Zhihua Wang, Xinpeng Guo, Yu Fan, Guanghu Luo, Xiujun Zhang, Hongyu Zheng","doi":"10.1186/s13287-025-04256-y","DOIUrl":"10.1186/s13287-025-04256-y","url":null,"abstract":"<p><strong>Background: </strong>Osteoporosis, which is a prevalent metabolic bone disease, is closely associated with imbalances in the gut microbiota.</p><p><strong>Methods: </strong>The ovaries of female 6-month-old Sprague-Dawley rats were surgically removed to induce osteoporosis. Subsequently, 16S rRNA sequencing was employed to characterize the gut microbiota in the osteoporotic rats. Bone marrow mesenchymal stem cells (BMSCs) were isolated from osteoporotic rats and cultured separately, and their osteogenic and adipogenic differentiation was observed. Furthermore, exosomes were extracted from these cells, and miRNA sequencing was performed on the exosomes to identify key miRNAs. Osteoporotic rats were then treated with a member of the gut microbiota, and changes in the osteogenic and adipogenic differentiation of BMSCs were observed.</p><p><strong>Results: </strong>In our investigation, we observed altered proportions of Firmicutes and Bacteroidetes in the guts of ovariectomized rats, which contributed to dysbiosis and subsequent changes in intestinal permeability. The BMSCs exhibited disrupted osteogenic/adipogenic differentiation, which was associated with structural damage to bones. Through the isolation of exosomes from BMSCs and subsequent miRNA analysis, we identified miR-151-3p and miR-23b-3p as potential pivotal regulators of bone metabolism. Furthermore, through 16S rRNA sequencing, we identified g_Ruminococcus and its marked capacity to ameliorate the imbalance in BMSC osteogenic/adipogenic differentiation. Intervention with g_Ruminococcus demonstrated promising outcomes, mitigating bone loss and structural damage to the tibia and femur in ovariectomized rats.</p><p><strong>Conclusions: </strong>These findings highlight the significant role of g_Ruminococcus in alleviating osteoporosis induced by estrogen deficiency, suggesting its therapeutic potential for addressing postmenopausal osteoporosis through the targeted modulation of BMSC-derived exosomal miR-151-3p and miR-23b-3p.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"143"},"PeriodicalIF":7.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658698","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":"Reviving hope: unlocking pancreatic islet immortality by optimizing a trehalose-based cryopreservation media and cell-penetrating peptide.","authors":"Zakieh Samsonchi, Roshanak Amirian, Lobat Tayebi, Hossein Derakhshankhah, Zhila Izadi, Ensiyeh Hajizadeh-Saffar","doi":"10.1186/s13287-025-04168-x","DOIUrl":"10.1186/s13287-025-04168-x","url":null,"abstract":"<p><strong>Background: </strong>Diabetes mellitus remains a pervasive global health concern, urging a deeper exploration of islet transplantation as a potential enduring solution. The efficacy of this therapeutic approach pivots on the precision of cryopreservation techniques, ensuring both the viability and accessibility of pancreatic islets. This study delves into the merits of cryopreserving these islets using the disaccharide trehalose, accompanied by an inventive strategy involving poly L proline (PLP) as a cell-penetrating peptide to overcome the cryoprotectant limitations inherent to trehalose.</p><p><strong>Methods: </strong>In our experiments with rat islets, we conducted meticulous viability assessments for fresh and frozen samples. We employed a spectrum of methods, including live/dead staining, insulin/glucagon staining, and measurement of reactive oxygen species (ROS) levels. To gauge functional integrity, we executed glucose-stimulated insulin secretion tests. Subsequently, we transplanted thawed islets into diabetic mice to scrutinize their performance in clinically relevant conditions.</p><p><strong>Results: </strong>Our study yielded compelling results, affirming the successful cryopreservation of pancreatic islets using trehalose and PLP. Viability, as corroborated through live/dead and insulin/glucagon staining, underscored the sustained preservation of frozen islets. Moreover, these preserved islets exhibited functional integrity by releasing insulin responsively to glucose stimulation. Significantly, upon transplantation into diabetic mice, the thawed islets proficiently restored euglycemia, evidenced by a substantial reduction in fasting blood glucose and an enhanced glucose tolerance.</p><p><strong>Conclusion: </strong>Our findings accentuate the potential of trehalose and PLP as sophisticated cryoprotectants for preserving pancreatic islets. Beyond highlighting viability and functionality, the preserved islets demonstrated a remarkable capacity to restore euglycemia post-transplantation. This research holds promise in addressing the inherent limitations of islet transplantation, particularly in the realm of Type 1 diabetes treatment.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"136"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626171","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":"Circ-AARS plays an important role during the odontogenic differentiation of dental pulp stem cells by modulating miR-24-3p/KLF6 expression.","authors":"Meizhi Sui, Jiaxuan Lyu, Jiaxin Zhou, Qian Liao, Zexu Xiao, Mingming Jin, Jiang Tao","doi":"10.1186/s13287-025-04239-z","DOIUrl":"10.1186/s13287-025-04239-z","url":null,"abstract":"<p><strong>Background: </strong>Circular RNAs (circRNAs) play a crucial role in stem cell-based tooth regeneration. However, the functions and underlying mechanisms of circRNAs in tooth regeneration from human dental pulp stem cells (DPSCs) remain largely unclear.</p><p><strong>Methods: </strong>In this study, DPSCs were used for odontogenic differentiation. High-throughput sequencing was performed for differential circRNA analysis. A luciferase reporter assay was conducted to confirm the downstream target of the circRNA, circ-AARS. We then constructed vectors and siRNAs for overexpressing and silencing circ-AARS, miR-24-3p, and Krüppel-like factor 6 (KLF6) and transfected them into DPSCs. Alkaline phosphatase staining, Alizarin Red S staining, western blotting assay, and quantitative reverse transcription-polymerase chain reaction were used to explore the underlying mechanisms of circ-AARS. Finally, a heterotopic bone model was utilized to reveal the regulating effects of circ-AARS.</p><p><strong>Results: </strong>High-throughput sequencing analysis showed that circ-AARS plays an important role during the odontogenic differentiation of DPSCs. Downregulation of circ-AARS inhibited the odontogenic differentiation of DPSCs; however, circ-AARS overexpression promoted their odontogenic differentiation. Bioinformatics analysis and luciferase reporter assay confirmed that both miR-24-3p and KLF6 were the downstream targets of circ-AARS. miR-24-3p downregulation or KLF6 overexpression restored the odontogenic differentiation ability of DPSCs after circ-AARS silencing. KLF6 upregulation restored the odontogenic differentiation ability of DPSCs after KLF6 overexpression. The heterotopic bone model confirmed that circ-AARS overexpression promoted the odontoblastic differentiation of DPSCs.</p><p><strong>Conclusion: </strong>The present study showed that circ-AARS can promote the odontoblastic differentiation of DPSCs by increasing KLF6 expression and sponging miR-24-3p. Taken together, the results indicate that circ-AARS may be a potential positive regulator of odontoblastic differentiation of DPSCs.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"137"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626167","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":"Small extracellular vesicles from young adipose-derived stem cells ameliorate age-related changes in the heart of old mice.","authors":"Jorge Sanz-Ros, Javier Huete-Acevedo, Cristina Mas-Bargues, Nekane Romero-García, Mar Dromant, Michel van Weeghel, Georges E Janssens, Consuelo Borrás","doi":"10.1186/s13287-025-04255-z","DOIUrl":"10.1186/s13287-025-04255-z","url":null,"abstract":"<p><strong>Background: </strong>Aging entails a progressive decline in physiological functions, elevating the risk of age-related diseases like heart failure or aortic stenosis. Stem cell therapies, especially those that use paracrine signaling, can potentially mitigate the adverse effects of aging.</p><p><strong>Objectives: </strong>The objective is to explore the potential of small extracellular vesicles (sEVs) derived from young adipose-derived stem cells (ADSC-sEVs) in reversing structural, molecular, and functional changes associated with aging in the heart.</p><p><strong>Methods: </strong>Aged C57BL/6J mice were treated intravenously with ADSC-sEVs from young mice or PBS as controls. Young mice were included to identify specific age-associated changes. The impact of sEV treatment on cardiac function was assessed using transthoracic echocardiography and physical endurance tests. Histological and molecular analyses were conducted on heart tissue to evaluate structural changes and markers of senescence, inflammation, and oxidative stress. A comprehensive metabolomic analysis was also performed on heart tissues to identify changes in metabolic profiles associated with aging and treatment status.</p><p><strong>Results: </strong>The administration of ADSC-sEVs significantly improves several aging-associated cardiac parameters, including oxidative stress, inflammation, and cellular senescence reductions. We also report on the age-related reversal of myocardial structure and function changes, highlighted by decreased fibrosis and improved vascularization. Notably, echocardiographic assessments reveal that sEV treatments ameliorate diastolic dysfunction and left ventricle structural alterations typically associated with aging. Furthermore, the treatment shifts the heart metabolome towards a more youthful profile.</p><p><strong>Conclusions: </strong>These results denote the potential of ADSC-sEVs as a novel, noninvasive therapeutic strategy for mitigating cardiac aging-associated functional decline.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"138"},"PeriodicalIF":7.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626174","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 cell-derived exosomes and miR-29a-3p mitigate renal fibrosis and vascular rarefaction after renal ischemia reperfusion injury.","authors":"Jing Huang, Lang Shi, Yifei Yang, Fan Zhao, Rengui Chen, Wenliang Liao, Jiefu Zhu, Dingping Yang, Xiongfei Wu, Shangting Han","doi":"10.1186/s13287-025-04226-4","DOIUrl":"10.1186/s13287-025-04226-4","url":null,"abstract":"<p><strong>Background: </strong>Renal fibrosis and vascular rarefaction are significant complications of ischemia/reperfusion (I/R) injury. Human umbilical cord mesenchymal cell-derived exosomes (hucMSC-exos) have shown potential in mitigating these conditions. This study investigates the role of miR-29a-3p in exosomes and its therapeutic effects on I/R-induced renal damage.</p><p><strong>Methods: </strong>Male C57BL/6 mice were subjected to unilateral renal ischemia for 28 min followed by reperfusion. Exosomes and miR-29a-3p mimics/inhibitors were injected into the mice. Renal function, histological analysis, and molecular assays were performed to evaluate fibrosis and vascular integrity.</p><p><strong>Results: </strong>Exosome treatment significantly improved renal function and reduced fibrosis and vascular rarefaction post-I/R. MiR-29a-3p was highly expressed in hucMSC-exos but reduced in renal fibrosis models. MiR-29a-3p mimic reduced, while its inhibitor exacerbated I/R-induced renal fibrosis and vascular rarefaction. Collagen I and TNFR1 were identified as direct targets of miR-29a-3p in fibroblasts and endothelial cells, respectively. Exosomes overexpressing miR-29a-3p provided superior protection compared to unmodified hucMSC-exos.</p><p><strong>Conclusion: </strong>HucMSC-exos, particularly those overexpressing miR-29a-3p, have potent therapeutic effects against renal fibrosis and vascular rarefaction post-I/R. MiR-29a-3p targets TNFR1 and collagen I, highlighting its potential in renal fibrosis therapy.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"135"},"PeriodicalIF":7.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617314","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":"Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer.","authors":"Shuna Chen, Chao Han, Zihan Shi, Xin Guan, Liyuan Cheng, Liang Wang, Wei Zou, Jing Liu","doi":"10.1186/s13287-025-04224-6","DOIUrl":"10.1186/s13287-025-04224-6","url":null,"abstract":"<p><strong>Background: </strong>Acute ischemic stroke (AIS) initiates secondary injuries that worsen neurological damage and hinder recovery. While peripheral immune responses play a key role in stroke outcomes, clinical results from immunotherapy have been suboptimal, with limited focus on T-cell dynamics. Umbilical mesenchymal stem cells (UMSCs) offer therapeutic potential due to their immunomodulatory properties. They can regulate immune responses and reduce neuroinflammation, potentially enhancing recovery by fostering a pro-regenerative peripheral immune environment. However, the effect of UMSCs on T-cell dynamics in AIS remains underexplored. This study investigates T-cell dynamics following AIS and examines how UMSCs may mitigate immune dysregulation to develop better treatment strategies.</p><p><strong>Methods: </strong>AIS patients (NIHSS scores 0-15) were recruited within 72 h of stroke onset, with peripheral blood samples collected on Day 0 (enrollment) and Day 7. T-cell compartments were identified by flow cytometry, and plasma cytokine levels were quantified using a cytometric bead array (CBA). Mitochondria in UMSCs were labeled with MitoTracker. Peripheral blood mononuclear cells from patients were isolated, treated with lipopolysaccharide (LPS), and cocultured with UMSCs in both direct contact and Transwell systems. Flow cytometry, CBA, RT-qPCR, and immunofluorescence assays were used to detect T-cell compartments, gene expression markers for helper T (Th) cell differentiation, cytokine profiles, mitochondrial transfer, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Additionally, mitochondrial DNA in UMSCs was depleted. The effects of UMSCs and mitochondria-depleted UMSCs on ischemic stroke mice were compared through behavioral assessments and analysis of the peripheral immune microenvironment.</p><p><strong>Results: </strong>In AIS, T-cell compartments underwent a phenotypic shift from naïve to effector or memory states, with a specific increase in Th17 cells and a decrease in regulatory T cells, leading to alterations in T-cell-mediated immune functions. In an ex vivo co-culture system, LPS stimulation further amplified these disparities, inducing mitochondrial dysfunction and oxidative stress in T cells. Notably, UMSCs restored mitochondrial function and reversed the shift in T-cell compartments through mitochondrial transfer. Critically, UMSC treatment significantly improved both neurological deficits and peripheral immune disorders in ischemic stroke mice, whereas mitochondria-depleted UMSCs failed to produce this effect.</p><p><strong>Conclusions: </strong>Our comprehensive insights into the key attributes of T-cell compartments in acute ischemic stroke and the immune regulatory mechanisms of UMSCs provide a crucial theoretical foundation for understanding peripheral immune disorders in ischemic stroke and the therapeutic potential of UMSC treatment.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"134"},"PeriodicalIF":7.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617316","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":"Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy.","authors":"Ming-Min Chang, Dinh Toi Chu, Sheng-Che Lin, Jung-Shun Lee, Thuy Duong Vu, Hue Thi Vu, Thamil Selvee Ramasamy, Shau-Ping Lin, Chia-Ching Wu","doi":"10.1186/s13287-025-04164-1","DOIUrl":"10.1186/s13287-025-04164-1","url":null,"abstract":"<p><strong>Background: </strong>Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency.</p><p><strong>Methods: </strong>ASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation.</p><p><strong>Results: </strong>Chitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery.</p><p><strong>Conclusion: </strong>Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"129"},"PeriodicalIF":7.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606521","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":"Modeling of lung organoid-based fibrosis for testing the sensitivity of anti-fibrotic drugs.","authors":"Heping Wang, Zhiyi Han, Yang Yang, Lei Liu, Yang Huang, Jiehua Chen, Yulei Wang, Zihao Liu, Lingguo Xin, Yunshan Zhao, Wenjian Wang","doi":"10.1186/s13287-025-04251-3","DOIUrl":"10.1186/s13287-025-04251-3","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary fibrosis models play crucial roles in research of pulmonary fibrosis and anti-fibrosis drug screening. Despite the establishment of several pulmonary fibrosis models including lung fibrosis animals, stem cell differentiation, pulmospheres and so on, the one that mimic the personalized native lung lacks.</p><p><strong>Methods: </strong>We here developed a lung organoid-based fibrosis (LOF) model from native lung tissue, and the potential of the LOFs for the sensitivity test of anti-fibrotic drugs was evaluated.</p><p><strong>Results: </strong>Our results showed that the LOFs could be self-organized from the lung organoids and the fibroblasts derived from native lung tissue. Histochemical examination demonstrated that the LOFs were characteristic of pulmonary fibrosis in structure. Single-cell sequencing (SCS) further revealed that the cell clusters mimicked fibrotic process at cellular and molecular levels in the LOFs. Drug sensitivity test indicated that the LOFs could not only be used to evaluate the efficacy of anti-fibrotic drugs, but also display their toxicity.</p><p><strong>Conclusions: </strong>We demonstrate that the LOFs represent an efficient fibrotic model that mimics faithfully the personalized characteristics of native lung tissue.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"132"},"PeriodicalIF":7.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606526","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}