Pub Date : 2025-11-07DOI: 10.1016/j.stem.2025.10.008
Lei Fan, Qi Tang, Yutong Wang, Hang Sun, Ge Li, Yi Yang, Huiying Zhu, Zhaoyuan Liu, He Wang, Hongyan Wang, Qing Jing, Christopher L. Antos, Hui Xiao, Renchu Guan, Gang Pei, Florent Ginhoux, Zhigang Zhou, An Zeng
Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we uncovered an injury-induced Clusterin+ cardiomyocyte (Clu+ CM) population that coordinates reparative, anti-inflammatory macrophage activity. Following injury, Clu+ CMs emerge in the border zone of regenerative hearts but are scarce in non-regenerative contexts. These CMs secrete CLU, which binds to macrophage Toll-like receptor 4 (TLR4), attenuating inflammation and promoting reparative polarization through Cpt1a-dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor, type 1A (BMPR1A) signaling in CMs to drive proliferation. Reduced CLU levels in myocardial infarction patients correlate with impaired cardiac function, whereas Clu overexpression or transplantation of engineered CLU+ human cardiac organoids recapitulates this regenerative modulation, enhancing myocardial repair in adult mice. Our findings reveal a critical cardio-immune mechanism whereby Clu+ CMs reprogram macrophages to resolve inflammation and stimulate CM proliferation, providing potential strategies for cardiac regeneration.
成人心脏损伤后会留下疤痕，而新生儿心脏会再生。这种二分法背后的机制尚不清楚。通过比较时空单细胞分析和双重组酶介导的谱系追踪，我们发现了一个损伤诱导的Clusterin+心肌细胞（Clu+ CM）群体，该群体协调修复、抗炎巨噬细胞的活性。损伤后，Clu+ CMs出现在再生心脏的边界区，但在非再生情况下很少出现。这些CMs分泌CLU， CLU与巨噬细胞toll样受体4 （TLR4）结合，通过cpt1a依赖性脂肪酸氧化减轻炎症并促进修复极化。这些巨噬细胞分泌骨形态发生蛋白2 (bone morphogenetic protein 2, BMP2)，激活CMs中骨形态发生蛋白受体1A型（bone morphogenetic protein receptor, type 1A, BMPR1A）信号，驱动细胞增殖。心肌梗死患者CLU水平降低与心功能受损相关，而CLU过表达或移植工程化的CLU+人类心脏类器官再现了这种再生调节，增强了成年小鼠的心肌修复。我们的研究结果揭示了一个关键的心脏免疫机制，通过Clu+ CMs重编程巨噬细胞来解决炎症和刺激CM增殖，为心脏再生提供了潜在的策略。
{"title":"Injury-induced Clusterin+ cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages","authors":"Lei Fan, Qi Tang, Yutong Wang, Hang Sun, Ge Li, Yi Yang, Huiying Zhu, Zhaoyuan Liu, He Wang, Hongyan Wang, Qing Jing, Christopher L. Antos, Hui Xiao, Renchu Guan, Gang Pei, Florent Ginhoux, Zhigang Zhou, An Zeng","doi":"10.1016/j.stem.2025.10.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.008","url":null,"abstract":"Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we uncovered an injury-induced Clusterin<sup>+</sup> cardiomyocyte (<em>Clu</em><sup>+</sup> CM) population that coordinates reparative, anti-inflammatory macrophage activity. Following injury, <em>Clu</em><sup>+</sup> CMs emerge in the border zone of regenerative hearts but are scarce in non-regenerative contexts. These CMs secrete CLU, which binds to macrophage Toll-like receptor 4 (TLR4), attenuating inflammation and promoting reparative polarization through <em>Cpt1a</em>-dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor, type 1A (BMPR1A) signaling in CMs to drive proliferation. Reduced CLU levels in myocardial infarction patients correlate with impaired cardiac function, whereas <em>Clu</em> overexpression or transplantation of engineered CLU<sup>+</sup> human cardiac organoids recapitulates this regenerative modulation, enhancing myocardial repair in adult mice. Our findings reveal a critical cardio-immune mechanism whereby <em>Clu</em><sup>+</sup> CMs reprogram macrophages to resolve inflammation and stimulate CM proliferation, providing potential strategies for cardiac regeneration.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"135 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-06DOI: 10.1016/j.stem.2025.10.002
Jiao Li, Shuyong Wang, Jie Yuan, Xiaoxu Mao, Xuan Wang, Lincheng Zhang, Qiulin Dong, Ziye Chen, Yunfang Wang, Nan Tang
Tissues are constantly exposed to stresses that cause both cellular and structural damage. In response, a coordinated healing process restores tissue integrity and functionality. When these stresses persist or the healing process becomes dysregulated, progressive tissue fibrosis can emerge. This condition is characterized by excessive scarring, disrupted tissue architecture, and loss of organ function. In this review, we explore the relationship between regeneration and fibrosis, with a focus on the lung and liver. We dissect cellular contributions and interplay among fibroblasts, epithelial progenitors, immune components, and vasculature in both regenerative and fibrotic responses to tissue injury. We also examine therapeutic strategies under development that navigate the complexities of immune mediators, fibrogenic myofibroblasts, and excess extracellular matrix (ECM) with small-molecule targeting and various cell-based approaches. By elucidating regulatory networks controlling regeneration and fibrosis, we aim to inform the development of targeted strategies to alleviate or reverse fibrosis, ultimately supporting long-term tissue health.
{"title":"Tissue regeneration: Unraveling strategies for resolving pathological fibrosis","authors":"Jiao Li, Shuyong Wang, Jie Yuan, Xiaoxu Mao, Xuan Wang, Lincheng Zhang, Qiulin Dong, Ziye Chen, Yunfang Wang, Nan Tang","doi":"10.1016/j.stem.2025.10.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.002","url":null,"abstract":"Tissues are constantly exposed to stresses that cause both cellular and structural damage. In response, a coordinated healing process restores tissue integrity and functionality. When these stresses persist or the healing process becomes dysregulated, progressive tissue fibrosis can emerge. This condition is characterized by excessive scarring, disrupted tissue architecture, and loss of organ function. In this review, we explore the relationship between regeneration and fibrosis, with a focus on the lung and liver. We dissect cellular contributions and interplay among fibroblasts, epithelial progenitors, immune components, and vasculature in both regenerative and fibrotic responses to tissue injury. We also examine therapeutic strategies under development that navigate the complexities of immune mediators, fibrogenic myofibroblasts, and excess extracellular matrix (ECM) with small-molecule targeting and various cell-based approaches. By elucidating regulatory networks controlling regeneration and fibrosis, we aim to inform the development of targeted strategies to alleviate or reverse fibrosis, ultimately supporting long-term tissue health.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"152 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-06DOI: 10.1016/j.stem.2025.09.012
Clare L. Parish
Low yields of dopamine neurons in human stem cell-derived neural grafts limit their potential for treating Parkinson’s disease. Zhang et al.1 develop a new three-dimensional differentiation method, informed and refined through careful clonal linage tracing of donor cells post-transplantation, to improve dopamine neuron purity of grafts, eliminating unwanted, off-target populations.
{"title":"Boosting dopamine: Following the lineage toward Parkinson’s repair","authors":"Clare L. Parish","doi":"10.1016/j.stem.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.012","url":null,"abstract":"Low yields of dopamine neurons in human stem cell-derived neural grafts limit their potential for treating Parkinson’s disease. Zhang et al.<span><span><sup>1</sup></span></span> develop a new three-dimensional differentiation method, informed and refined through careful clonal linage tracing of donor cells post-transplantation, to improve dopamine neuron purity of grafts, eliminating unwanted, off-target populations.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"53 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-06DOI: 10.1016/j.stem.2025.10.007
Renee C. Ryals
The number of retinal pigment epithelium (RPE) transplantation clinical trials for dry age-related macular degeneration (AMD) is increasing quickly, with groups using different stem cell sources, delivery approaches, and immune suppression. We discuss the recent success in a phase 1/2a clinical trial1 evaluating allogeneic RPE stem cell-derived RPE cells isolated from the RPE layer of human cadaveric eyes.
{"title":"RPE replacement therapy for dry AMD—early success in a phase 1/2 clinical trial","authors":"Renee C. Ryals","doi":"10.1016/j.stem.2025.10.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.007","url":null,"abstract":"The number of retinal pigment epithelium (RPE) transplantation clinical trials for dry age-related macular degeneration (AMD) is increasing quickly, with groups using different stem cell sources, delivery approaches, and immune suppression. We discuss the recent success in a phase 1/2a clinical trial<span><span><sup>1</sup></span></span> evaluating allogeneic RPE stem cell-derived RPE cells isolated from the RPE layer of human cadaveric eyes.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"32 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1016/j.stem.2025.10.006
Lu Wang, Yuji Nakamura, Junhao Li, David Sievert, Yang Liu, Toan Nguyen, Prudhvi Sai Jetti, Ethan Thai, Rachel Yibei Zhou, Jiaming Weng, Naomi Meave, Manya Yadavilli, Robyn Howarth, Kevin Camey, Niyati Banka, Charlotte Owusu-Hammond, Chelsea Barrows, Stephen F. Kingsmore, Maha S. Zaki, Eran Mukamel, Joseph G. Gleeson
Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.
{"title":"A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders","authors":"Lu Wang, Yuji Nakamura, Junhao Li, David Sievert, Yang Liu, Toan Nguyen, Prudhvi Sai Jetti, Ethan Thai, Rachel Yibei Zhou, Jiaming Weng, Naomi Meave, Manya Yadavilli, Robyn Howarth, Kevin Camey, Niyati Banka, Charlotte Owusu-Hammond, Chelsea Barrows, Stephen F. Kingsmore, Maha S. Zaki, Eran Mukamel, Joseph G. Gleeson","doi":"10.1016/j.stem.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.006","url":null,"abstract":"Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"74 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1016/j.stem.2025.10.004
Da Wang, Xinyue Zhang, Xiao-Yan Tang, Yixia Gan, Hanwen Yu, Shanshan Wu, Yuan Hong, Mengdan Tao, Chu Chu, Xiaoxuan Qi, Hao Hu, Yimin Zhu, Wanying Zhu, Xiao Han, Min Xu, Yi Dong, Qing Cheng, Xing Guo, Yan Liu
The nucleus basalis of Meynert (nbM), the major cholinergic output of the basal forebrain, regulates cortical modulation, learning, and memory. Dysfunction of the nbM-cortical cholinergic pathway is implicated in neurodegenerative and neurodevelopmental disorders, including Alzheimer’s disease (AD) and Down syndrome (DS). Here, we generated human nbM organoids (hnbMOs) from human pluripotent stem cells (hPSCs) containing functional cholinergic projection neurons. Then we reconstructed long-distance cholinergic projections from nbM to the cortex by co-culturing hnbMOs with human fetal brains and transplanting hnbMOs into immunodeficient mice. We further established nbM-cortical assembloids by fusing hnbMOs with human cortical organoids (hCOs). We also established a human-specific cholinergic projection system in transplanted assembloids. Using viral tracing and functional assays, we validated that cholinergic neurons send projections into hCOs and form synaptic connections. Moreover, we captured projection deficits in DS-derived assembloids, demonstrating the utility of this model for studying nbM-related neural circuits and neurological disorders.
{"title":"Generation of human nucleus basalis organoids with functional nbM-cortical cholinergic projections in transplanted assembloids","authors":"Da Wang, Xinyue Zhang, Xiao-Yan Tang, Yixia Gan, Hanwen Yu, Shanshan Wu, Yuan Hong, Mengdan Tao, Chu Chu, Xiaoxuan Qi, Hao Hu, Yimin Zhu, Wanying Zhu, Xiao Han, Min Xu, Yi Dong, Qing Cheng, Xing Guo, Yan Liu","doi":"10.1016/j.stem.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.004","url":null,"abstract":"The nucleus basalis of Meynert (nbM), the major cholinergic output of the basal forebrain, regulates cortical modulation, learning, and memory. Dysfunction of the nbM-cortical cholinergic pathway is implicated in neurodegenerative and neurodevelopmental disorders, including Alzheimer’s disease (AD) and Down syndrome (DS). Here, we generated human nbM organoids (hnbMOs) from human pluripotent stem cells (hPSCs) containing functional cholinergic projection neurons. Then we reconstructed long-distance cholinergic projections from nbM to the cortex by co-culturing hnbMOs with human fetal brains and transplanting hnbMOs into immunodeficient mice. We further established nbM-cortical assembloids by fusing hnbMOs with human cortical organoids (hCOs). We also established a human-specific cholinergic projection system in transplanted assembloids. Using viral tracing and functional assays, we validated that cholinergic neurons send projections into hCOs and form synaptic connections. Moreover, we captured projection deficits in DS-derived assembloids, demonstrating the utility of this model for studying nbM-related neural circuits and neurological disorders.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"4 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1016/j.stem.2025.10.005
Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Nancy C. Allen, Tsukasa Kadota, Andrew Lechner, Ritusree Biswas, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Tatsuya Tsukui, Vincent Auyeung, Aaron S. Mansfield, Lindsay M. LaFave, Tien Peng
Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.
{"title":"Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity","authors":"Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Nancy C. Allen, Tsukasa Kadota, Andrew Lechner, Ritusree Biswas, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Tatsuya Tsukui, Vincent Auyeung, Aaron S. Mansfield, Lindsay M. LaFave, Tien Peng","doi":"10.1016/j.stem.2025.10.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.005","url":null,"abstract":"Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify <em>p16</em><sup><em>Ink4a</em></sup>+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by <em>p16</em><sup><em>Ink4a</em></sup>+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our <em>ex vivo</em> senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears <em>p16</em><sup><em>Ink4a</em></sup>+ cancer-associated fibroblasts <em>in vivo</em>. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"22 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yolk-sac-derived embryonic cardiac tissue-resident macrophages (TRMPs) colonize the heart early in development and are essential for proper heart development, supporting tissue remodeling, angiogenesis, electrical conduction, efferocytosis, and immune regulation. We present here a human heart-macrophage assembloid (hHMA) model by integrating autologous human pluripotent stem cell (hPSC)-derived embryonic monocytes into heart organoids to generate physiologically relevant TRMPs that persist long-term and contribute to cardiogenesis. Using single-cell transcriptomics, live imaging, and proteomics, we demonstrate that TRMPs modulate cardiac paracrine signaling, perform efferocytosis, and regulate extracellular matrix remodeling and electrical conduction. In a proof-of-concept maturated hHMA model of chronic inflammation, TRMPs adopt pro-inflammatory phenotypes that promote arrhythmogenic activity, consistent with atrial fibrillation through activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. This system enables detailed mechanistic studies of immune-cardiac interactions and provides a powerful in vitro platform for modeling human heart development and inflammation-driven arrhythmias.
{"title":"Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling.","authors":"Colin O'Hern,Sammantha Caywood,Shakhlo Aminova,Artem Kiselev,Brett Volmert,Weiheng Cao,Fei Wang,Mia Dionise,Merlinda-Loriane Sewavi,Milana Skoric,Hussain Basrai,Freyda Mannering,Priyadharshni Muniyandi,Mirel Popa,George Boulos,Kyle Wolf,Izabelle Brown,Isabel Nuñez-Regueiro,Amanda Huang,Aleksandra Kostina,Lauren Squire,Curtis Wilkerson,Nagib Chalfoun,Sangbum Park,Nureddin Ashammakhi,Chao Zhou,Christopher Contag,Aitor Aguirre","doi":"10.1016/j.stem.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.011","url":null,"abstract":"Yolk-sac-derived embryonic cardiac tissue-resident macrophages (TRMPs) colonize the heart early in development and are essential for proper heart development, supporting tissue remodeling, angiogenesis, electrical conduction, efferocytosis, and immune regulation. We present here a human heart-macrophage assembloid (hHMA) model by integrating autologous human pluripotent stem cell (hPSC)-derived embryonic monocytes into heart organoids to generate physiologically relevant TRMPs that persist long-term and contribute to cardiogenesis. Using single-cell transcriptomics, live imaging, and proteomics, we demonstrate that TRMPs modulate cardiac paracrine signaling, perform efferocytosis, and regulate extracellular matrix remodeling and electrical conduction. In a proof-of-concept maturated hHMA model of chronic inflammation, TRMPs adopt pro-inflammatory phenotypes that promote arrhythmogenic activity, consistent with atrial fibrillation through activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. This system enables detailed mechanistic studies of immune-cardiac interactions and provides a powerful in vitro platform for modeling human heart development and inflammation-driven arrhythmias.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"352 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The low in vivo yield of midbrain dopaminergic (mDA) neurons and uncertain lineage fates of donor cells following transplantation impede clinical application of human pluripotent stem cell (hPSC)-based cell therapy for Parkinson's disease (PD). We developed a three-dimensional (3D) differentiation method, SphereDiff, to generate high-purity mDA progenitors (mDAPs), leading to a significant enrichment of mDA neurons post transplantation. Grafted mDA neurons fully restored dopamine levels and corrected motor deficits in PD model mice. Single-cell spatial transcriptomics revealed a patterned distribution of mDA neuron subtypes and glial cells. Using cross-transplantation single-cell split barcoding (TX-SISBAR), we elucidated the clonal lineage fates of donor cells post transplantation, revealing the mDA neuron and astrocyte fates of mDAPs and glutamatergic neuron fates of diencephalic progenitors. Leveraging these lineage insights, we further refined SphereDiff and eliminated off-target lineage cells. Producing high in vivo efficacy, lineage-defined donor cells supports safer and more effective PD cell therapy in regenerative medicine.
{"title":"3D-generation of high-purity midbrain dopaminergic progenitors and lineage-guided refinement of grafts supports Parkinson's disease cell therapy.","authors":"Xinyue Zhang,Ziyan Wu,Hui He,Qian Guan,Qike Ouyang,Rongjing Wang,Lianshun Xie,Yingying Zhou,Ban Feng,Zinan Luo,Peibo Xu,Wei Yan,Gang Hu,Jun Li,Meiling Zhang,Yuqiao Zou,Xiangjie Xu,Changyin Zhou,Qian Cheng,Jun Liu,Qinqin Gao,Shanzheng Yang,Man Xiong,Yuejun Chen","doi":"10.1016/j.stem.2025.10.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.001","url":null,"abstract":"The low in vivo yield of midbrain dopaminergic (mDA) neurons and uncertain lineage fates of donor cells following transplantation impede clinical application of human pluripotent stem cell (hPSC)-based cell therapy for Parkinson's disease (PD). We developed a three-dimensional (3D) differentiation method, SphereDiff, to generate high-purity mDA progenitors (mDAPs), leading to a significant enrichment of mDA neurons post transplantation. Grafted mDA neurons fully restored dopamine levels and corrected motor deficits in PD model mice. Single-cell spatial transcriptomics revealed a patterned distribution of mDA neuron subtypes and glial cells. Using cross-transplantation single-cell split barcoding (TX-SISBAR), we elucidated the clonal lineage fates of donor cells post transplantation, revealing the mDA neuron and astrocyte fates of mDAPs and glutamatergic neuron fates of diencephalic progenitors. Leveraging these lineage insights, we further refined SphereDiff and eliminated off-target lineage cells. Producing high in vivo efficacy, lineage-defined donor cells supports safer and more effective PD cell therapy in regenerative medicine.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"39 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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