Stem Cell Research & Therapy最新文献

{"title":"DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy.","authors":"Jinjin Ma, Xinyu Wang, Dalei Sun, Jiali Chen, Linyi Zhou, Kaiao Zou, Xinxin Ni, Hongting Jin, Jun Lin","doi":"10.1186/s13287-025-04468-2","DOIUrl":"10.1186/s13287-025-04468-2","url":null,"abstract":"","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"356"},"PeriodicalIF":7.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592371","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":"High-activity placenta-derived mesenchymal stem cells combined with low-intensity extracorporeal shock wave therapy for diabetic erectile dysfunction: a prospective randomized controlled trial.","authors":"Yun-Hua Ji, Yi-Fan Zhang, Xiao Tan, Hao-Zhong Hou, Zhen Yao, Bo Zhang","doi":"10.1186/s13287-025-04499-9","DOIUrl":"10.1186/s13287-025-04499-9","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the efficacy and safety of high-activity placenta-derived mesenchymal stem cells (hPMSCs) in combination with low-intensity extracorporeal shock wave therapy (LI-ESWT) for the treatment of diabetic erectile dysfunction (ED).</p><p><strong>Methods: </strong>This prospective, randomized, controlled clinical trial enrolled 33 patients with refractory diabetic ED. Participants were randomly assigned in a 1:1:1 ratio to one of three groups: the hPMSCs group, the LI-ESWT group, or the combined therapy group (H + L). All subjects discontinued ED medications for at least two weeks prior to receiving the intervention. Treatment efficacy was assessed at baseline and at 1,3 and 6 months post-intervention using the International Index of Erectile Function - Erectile Function (IIEF-EF), Erection Hardness Score (EHS), Sexual Encounter Profile (SEP-2/SEP-3), and Rigiscan parameters, with safety outcomes monitored concurrently.</p><p><strong>Results: </strong>At the 6-month follow-up, the combined therapy group demonstrated significantly superior outcomes compared to the individual hPMSCs and LI-ESWT groups. Specifically, total erection time reached 22.20 (15.20, 30.25) minutes (p = 0.001) and full erection time reached 11.90 (11.55, 12.35) minutes (p = 0.004) in the combined group. Moreover, EHS scores improved markedly, with 70% of patients in the combined group achieving an EHS > 2 at 6 months (p = 0.045). No severe adverse events were observed in any group; any local mild pain resolved within one week.</p><p><strong>Conclusion: </strong>The combination of high-activity hPMSCs and LI-ESWT appears to be a safe and effective strategy for improving erectile function in patients with diabetic ED, demonstrating a synergistic effect in prolonging erection duration and enhancing penile hardness. This combined therapeutic approach represents a promising new option for the clinical management of diabetic ED, warranting further validation in larger, multi-center studies to confirm its long-term efficacy and safety.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"359"},"PeriodicalIF":7.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592372","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":"In-vitro immunomodulatory efficacy of extracellular vesicles derived from TGF-β1/IFN-γ dual licensed human bone marrow mesenchymal stromal cells.","authors":"Jiemin Wang, Seyedmohammad Moosavizadeh, Manon Jammes, Abbas Tabasi, Trung Bach, Aideen E Ryan, Thomas Ritter","doi":"10.1186/s13287-025-04476-2","DOIUrl":"10.1186/s13287-025-04476-2","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stromal cells (MSCs) possess strong immunomodulatory properties, making them attractive candidates for regenerative medicine and immune-related therapies. Pre-activation, or licensing, of MSCs with cytokines such as interferon-gamma (IFN-γ) and transforming growth factor-beta 1 (TGF-β1) has been shown to enhance their immunosuppressive efficacy. Recent attention has turned to extracellular vesicles (EVs) released by licensed MSCs as a cell-free therapeutic alternative.</p><p><strong>Methods: </strong>Small EVs were isolated from MSCs licensed with a combination of IFN-γ and TGF-β1. These EVs were characterized according to standardized criteria. Their immunomodulatory effects were assessed in vitro using two human immune models: a THP-1-derived macrophage polarization system and a peripheral blood mononuclear cell (PBMC) co-culture assay. Pro/anti-inflammatory molecules secretion, T cell proliferation, and regulatory T cell induction were quantified. Dimensionality reduction using t-distributed stochastic neighbor embedding (t-SNE) was applied to multiparametric flow cytometry data for immune profiling. In addition, publicly available transcriptomic datasets (GSE122091 and GSE46019) were analyzed to identify differentially expressed genes (DEGs) in IFN-γ- and TGF-β1-licensed MSCs, providing insight into potential molecular drivers of EV-mediated immunoregulation.</p><p><strong>Results: </strong>Licensed EVs significantly inhibited pro-inflammatory THP-1 macrophage activation and promoted an anti-inflammatory phenotype, with reduced secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), increased IL-10 production, and decreased nitric oxide (NO) levels.. Compared to EVs from non-licensed MSCs, licensed EVs induced a greater proportion of regulatory T cells and exhibited enhanced suppression of allogeneic T cell proliferation. t-SNE analysis revealed a distinct immunoregulatory signature induced by licensed EVs, characterized by the emergence of a non-proliferative lymphocyte subset with elevated co-expression of CD4, CD25, and FOXP3. Transcriptomic analysis further revealed seven overlapping DEGs between IFN-γ- and TGF-β1-licensed MSCs, including both upregulated (GPR68, LIMK2, LIPG) and downregulated (EFNA5, PRKG1, DCLK1, TRIM2) genes, several of which are functionally implicated in EV-mediated immune regulation.</p><p><strong>Conclusions: </strong>Small EVs derived from IFN-γ and TGF-β1-licensed MSCs exhibit demonstrate dose-dependent immunomodulatory trends in vitro, with enhanced effects observed at higher concentrations.. These findings suggest their potential utility in modulating both innate and adaptive immune responses, warranting further investigation for their application as a cell-free therapeutic strategy in immune-mediated conditions.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"357"},"PeriodicalIF":7.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592373","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":"Review: progression and heterogeneity of multiple sources of mesenchymal stromal cells for the treatment of rheumatoid arthritis.","authors":"Shiyi Wu, Shuaijie Ding, Yu Wang, Shinan Li, Zhenhua Ying","doi":"10.1186/s13287-025-04515-y","DOIUrl":"10.1186/s13287-025-04515-y","url":null,"abstract":"<p><p>Rheumatoid arthritis is often a neglected autoimmune disease characterized by inflammation and destruction of the joints leading to pain, swelling and restricted movement, particularly affecting specific population groups and severely reducing the quality of life of patients. Certain risk factors (smoking, diet, infections) contribute to the increased prevalence of the disease in patients, with targeted interventions to alleviate symptoms. Due to the complexity of current medications and the lack of a systematic approach to decision-making, Mesenchymal stromal cells therapy has become increasingly popular in recent years. It plays different roles in different diseases, especially in Rheumatoid arthritis, stromal cells have shown promising therapeutic potential for tissue repair and regeneration, immunomodulation and anti-inflammatory effects. This paper provides a systematic review of our current understanding of the regulatory mechanisms, heterogeneity, and cell engineering modifications of stromal cells from multiple sources.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"358"},"PeriodicalIF":7.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose-derived stem cells alleviate acute pancreatitis by inhibiting ferroptosis and oxidative damage in canines.","authors":"Yansong Ge, Mingzhen Chen, Meilin Li, Zheng Wang, Ruxin Ding, Zhiying Wan, Enshuang Xu, Jiasan Zheng","doi":"10.1186/s13287-025-04466-4","DOIUrl":"10.1186/s13287-025-04466-4","url":null,"abstract":"<p><strong>Background: </strong>Acute pancreatitis (AP) is a common exocrine pancreatic disease that can lead to systemic inflammatory response syndrome and multiorgan failure in canines. The therapeutic benefits of adipose-derived stem cells (ADSCs) and conditioned medium (CM) and the role in ferroptosis regulation in managing AP in canines (dogs) were investigated in this study.</p><p><strong>Methods: </strong>Sixteen dogs were randomly divided into a control (CON), AP, ADSC, or ADSC-CM group. The AP model was established by injecting the dogs with sodium taurocholate (5%, 0.1 mL/kg) and trypsin (3500 U/kg) via the pancreaticobiliary duct. ADSCs (1 × 10⁶/kg) and CM (0.1 mL/kg) were injected intravenously 6 h after surgery, and the roles on ferroptosis and oxidative stress were analyzed. The changing patterns of ferroptosis and oxidative stress were determined in vitro using a lipopolysaccharideinduced cellular inflammation model of AR42J.</p><p><strong>Results: </strong>Ferroptosis occurred in the pancreas during AP, as evidenced by significant iron accumulation, suppressed glutathione peroxidase (GPx)4 expression, and increased transferrin receptor-1 (TFR1), and ferritin heavy chain expression. Treatment with ADSCs and ADSC-CM led to pathological remission and effectively restored abnormal amylase and lipase levels. ADSC-CM showed ferroptosis-alleviating effects similar to that of ADSCs, with reduced iron accumulation and increased GPx4 expression. Furthermore, ADSCs could promote the nuclear translocation of nuclear factor erythroid 2-related factor 2 and initiate the transcription of detoxification enzymes to protect the pancreas from oxidative damage.</p><p><strong>Conclusions: </strong>ADSCs can protect the pancreas of dogs by inhibiting ferroptosis and oxidative stress via paracrine function, indicating immense potential as a therapeutic target for treating AP.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"355"},"PeriodicalIF":7.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584924","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":"Correction: Interleukin-1 receptor antagonist overexpression in mesenchymal stem cells improves hemorrhagic cystitis outcomes via HtrA serine peptidase 3.","authors":"Jialin Song, Yanxiao Han, Yuyan Chen, Lin Cheng, Juan Xiao, Ai Li, Dexiao Kong, Yang Jiang, Chengyun Zheng","doi":"10.1186/s13287-025-04494-0","DOIUrl":"10.1186/s13287-025-04494-0","url":null,"abstract":"","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"353"},"PeriodicalIF":7.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584925","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":"Stepwise differentiation of airway epithelial cells from human tonsil-derived mesenchymal stem cells.","authors":"Ha Yeong Kim, Jiin Yang, Han Su Kim, Soo Yeon Jung","doi":"10.1186/s13287-025-04397-0","DOIUrl":"10.1186/s13287-025-04397-0","url":null,"abstract":"<p><strong>Background: </strong>Airway defects, often resulting from tumor resection, trauma, or infection, pose significant treatment challenges owing to the intricate, multilayered structure of the airway. Successful recovery depends on reconstructing the respiratory epithelium, the lining next to the cartilage. Although autologous epithelial or progenitor cells are used to reconstruct the epithelium, they are not ideal for regeneration because of difficulties in expansion and differentiation in vitro. In this study, we developed an alternative approach to respiratory epithelial regeneration using human tonsil-derived mesenchymal stem cells (TMSCs) to induce epithelial cell differentiation through a stepwise process.</p><p><strong>Methods: </strong>TMSCs were isolated from the human tonsillar tissues of patients undergoing tonsillectomy and differentiated into airway epithelial cells following human embryonic development. To generate airway epithelial cells, TMSCs were exposed to various chemical agents or protein combinations during a 4-step process.</p><p><strong>Results: </strong>We observed that TMSCs can be induced into the definitive endoderm (DE) with a low concentration of activin A, activating the Nodal/TGF-β signaling pathway. Subsequently, a combination of growth factors regulating BMP, TGF-β, and Wnt signaling induces the differentiation of TMSC-derived DE cells into anterior foregut endoderm, identified by upregulating PAX9, SOX2, and GATA3 gene expression. In the final 3-4 steps, an environment rich in Wnt and FGFs differentiated TMSCs into airway epithelial cells through lung progenitor cells, as evidenced by the increased gene expression of lung progenitor cell markers (NKX2-1), airway cell markers (KRT5), and ciliated cell markers (FoxJ1). Specifically, TMSC-derived airway epithelial cells exhibited a columnar epithelial structure resembling an F-actin filament structure.</p><p><strong>Conclusions: </strong>Our results demonstrated that TMSC-derived airway epithelial cells can be generated through stepwise differentiation and represent a potential alternative for the functional recovery of respiratory defects.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"354"},"PeriodicalIF":7.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584926","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":"Therapeutic effects of adipose tissue-derived mesenchymal stem cells on ER stress in a murine model of metabolic dysfunction-associated steatohepatitis: an in vivo and in vitro study.","authors":"Norihiko Ogawa, Akihiro Seki, Alessandro Nasti, Ho Yagi, Masatoshi Yamato, Hiiro Inui, Hiroki Nomura, Takuya Komura, Hidetoshi Nakagawa, Kouki Nio, Hajime Takatori, Tetsuro Shimakami, Masao Honda, Shuichi Kaneko, Yoshio Sakai, Taro Yamashita","doi":"10.1186/s13287-025-04482-4","DOIUrl":"10.1186/s13287-025-04482-4","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasing concern due to lifestyle changes, with metabolic dysfunction-associated steatohepatitis (MASH) leading to progressive liver damage, cirrhosis, and increased morbidity. The role of endoplasmic reticulum (ER) stress, particularly the unfolded protein response (UPR) pathway, in MASH progression remains unclear. Adipose tissue-derived stem cells (ADSCs) have shown promise in regenerative therapy; however, their mechanism for alleviating MASH-induced liver damage is not fully understood. In this study, we aimed to investigate the therapeutic mechanism of ADSCs in MASH, focusing on their modulation of ER stress in hepatocytes.</p><p><strong>Methods: </strong>C57BL/6J mice were fed either an atherogenic high-fat diet (AT + HF) or a high-fat diet (HFD-60) to induce MASH and simple steatosis (SS), respectively. Liver tissues were analyzed for gene expression, protein levels, and apoptotic markers using DNA microarray, quantitative PCR, western blotting, histological staining, and caspase activity assays. ADSCs were harvested, cultured, and treated to assess their effects on ER stress. In vitro experiments investigated palmitic acid-induced ER stress in hepatocytes and the effects of ADSCs on hepatic stellate cells and inflammatory markers.</p><p><strong>Results: </strong>The PERK arm of the UPR pathway was significantly upregulated in MASH liver tissues compared to SS tissues, correlating with increased apoptosis. ADSC administration reduced PERK activation, decreased apoptotic marker expression, and ameliorated hepatic fibrosis. However, ADSCs did not directly attenuate palmitic acid-induced ER stress in hepatocytes in vitro. Instead, they modulated the hepatic microenvironment by reducing hepatic stellate cell activation and IL-17-associated inflammation, indirectly mitigating ER stress and hepatocyte apoptosis.</p><p><strong>Conclusions: </strong>ADSCs alleviate MASH progression by modulating ER stress via immunomodulation rather than through directly rescuing hepatocytes. These findings highlight the potential of ADSCs as an immunomodulatory therapeutic strategy for MASH and support further investigation into their clinical application.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"349"},"PeriodicalIF":7.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576317","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":"Airway epithelial stem cell renewal and differentiation: overcoming challenging steps towards clinical-grade tissue engineering.","authors":"Davide Adamo, Vincenzo Giuseppe Genna, Giulia Galaverni, Chiara Chiavelli, Alessia Merra, Fabio Lepore, Federica Boraldi, Daniela Quaglino, Jessica Evangelista, Filippo Lococo, Graziella Pellegrini","doi":"10.1186/s13287-025-04478-0","DOIUrl":"10.1186/s13287-025-04478-0","url":null,"abstract":"<p><strong>Background: </strong>Despite their life-saving potential, tissue engineering approaches for the treatment of extensive tracheal and bronchial defects still face significant limitations. A major challenge is the inability to regenerate a functional airway epithelium containing the appropriate amount of stem cells required for long-term tissue renewal following transplantation of the bioengineered graft. In this scenario, extensive cell culture characterization, validation assays and quality controls are needed to guide each step of the regeneration process.</p><p><strong>Methods: </strong>Stem cell depletion is often due to suboptimal culture conditions, therefore we tested the ability of a clinical-grade culture system to support the safe and efficient in vitro expansion and differentiation of primary human tracheal and bronchial epithelial cells. Single-cell clonal analysis was used to unravel the heterogeneity of airway basal cells and to understand tissue-specific regeneration and differentiation mechanisms. Functional assays were used to investigate the wound healing ability and tightness of the regenerated epithelium under the selected culture conditions.</p><p><strong>Results: </strong>Primary tracheobronchial epithelial cells showed an impressive proliferative potential, allowing the regeneration of a mature and functional epithelium without immortalisation events. Analysis at the single cell level allowed the identification of the subpopulation of basal cells endowed with in vitro self-renewal, distinguishing them from transient amplifying cells. This approach has further defined the hierarchy of cellular differentiation and its correlation with regenerative and differentiation potential.</p><p><strong>Conclusions: </strong>Our results show that primary airway epithelial cell cultures can maintain stem cells together with their differentiation lineages in vitro. Airway cells can be safely and effectively used in autologous tissue engineering approaches when cultured under appropriate and well-standardised conditions. In addition to the validation assays proposed for the development of new advanced therapy products, this study outlines possible quality controls to enhance therapeutic success and maximise patient safety in future clinical applications.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"351"},"PeriodicalIF":7.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576314","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":"Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy.","authors":"Jiabin Qin, Qiangbing Yang, Asier Ullate-Agote, Vasco Sampaio-Pinto, Laura Florit, Inge Dokter, Chrysoula Mathioudaki, Lotte Middelberg, Pilar Montero-Calle, Paula Aguirre-Ruiz, Joana de Las Heras Rojo, Zhiyong Lei, Zeping Qiu, Jin Wei, Pim van der Harst, Felipe Prosper, Manuel M Mazo, Olalla Iglesias-García, Monique C Minnema, Joost P G Sluijter, Marish I F J Oerlemans, Alain van Mil","doi":"10.1186/s13287-025-04464-6","DOIUrl":"10.1186/s13287-025-04464-6","url":null,"abstract":"<p><strong>Background: </strong>Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery.</p><p><strong>Methods and results: </strong>Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils.</p><p><strong>Conclusions: </strong>Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"352"},"PeriodicalIF":7.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576318","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}