Pub Date : 2026-01-08DOI: 10.1016/j.stem.2025.12.003
Yun Zhao,Xi Wang,Kai Wang
In this issue of Cell Stem Cell, Zhang et al. identify a pathological NTRK2 isoform switch in bronchopulmonary dysplasia that alters the regenerative capacity of capillary endothelial cells, highlighting isoform-specific targeting as a promising strategy for vascular repair.1.
{"title":"Two isoforms, two outcomes: How NTRK2 shapes vascular regeneration.","authors":"Yun Zhao,Xi Wang,Kai Wang","doi":"10.1016/j.stem.2025.12.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.003","url":null,"abstract":"In this issue of Cell Stem Cell, Zhang et al. identify a pathological NTRK2 isoform switch in bronchopulmonary dysplasia that alters the regenerative capacity of capillary endothelial cells, highlighting isoform-specific targeting as a promising strategy for vascular repair.1.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"244 1","pages":"7-9"},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937753","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 : 2026-01-08DOI: 10.1016/j.stem.2025.12.016
Federico Midena, Laura Alessandrini, Claudio Conci, Matteo Barcella, Francesco Gazzo, Emanuela Jacchetti, Edoardo Carsana, Fabrizio Benedicenti, Roberta Vacca, Lucrezia della Volpe, Sergio Arévalo, Kety Giannetti, Dafne Barozzi, Martina Franchino, Erika Zonari, Francesca Ferrua, Giacomo Farina, Chiara Brombin, Federica Cugnata, Martina Fiumara, Raffaella Di Micco
Ex vivo culture of hematopoietic stem and progenitor cells (HSPCs) is required for gene therapy applications but inadvertently triggers detrimental cellular responses, potentially threatening clinical success. In this study, we employ nichoids, biocompatible 3D culture substrates with cell-scale resolution, to provide HSPCs with mechanical support during ex vivo manipulation. This innovative 3D system improves HSPC multi-lineage differentiation and engraftment capacity by leveraging mechanobiological control over nuclear morphology, cytoskeleton organization, metabolism, and DNA integrity. Notably, 3D culture enables efficient genetic engineering across multiple platforms, including long-range gene editing, base- and prime-editing, and lentiviral-mediated gene addition. Moreover, this scaffold increases the clonal output and persistence of genetically engineered cells in xenotransplantation experiments, including a clinical protocol for lentiviral gene addition in Wiskott-Aldrich syndrome. Overall, we propose a transformative approach to enhance the efficacy and safety of emerging and established hematopoietic stem cell-based gene therapy applications.
{"title":"Nanoengineered 3D culture substrate enables superior persistence and polyclonal engraftment of genetically engineered hematopoietic stem cells","authors":"Federico Midena, Laura Alessandrini, Claudio Conci, Matteo Barcella, Francesco Gazzo, Emanuela Jacchetti, Edoardo Carsana, Fabrizio Benedicenti, Roberta Vacca, Lucrezia della Volpe, Sergio Arévalo, Kety Giannetti, Dafne Barozzi, Martina Franchino, Erika Zonari, Francesca Ferrua, Giacomo Farina, Chiara Brombin, Federica Cugnata, Martina Fiumara, Raffaella Di Micco","doi":"10.1016/j.stem.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.016","url":null,"abstract":"<em>Ex vivo</em> culture of hematopoietic stem and progenitor cells (HSPCs) is required for gene therapy applications but inadvertently triggers detrimental cellular responses, potentially threatening clinical success. In this study, we employ nichoids, biocompatible 3D culture substrates with cell-scale resolution, to provide HSPCs with mechanical support during <em>ex vivo</em> manipulation. This innovative 3D system improves HSPC multi-lineage differentiation and engraftment capacity by leveraging mechanobiological control over nuclear morphology, cytoskeleton organization, metabolism, and DNA integrity. Notably, 3D culture enables efficient genetic engineering across multiple platforms, including long-range gene editing, base- and prime-editing, and lentiviral-mediated gene addition. Moreover, this scaffold increases the clonal output and persistence of genetically engineered cells in xenotransplantation experiments, including a clinical protocol for lentiviral gene addition in Wiskott-Aldrich syndrome. Overall, we propose a transformative approach to enhance the efficacy and safety of emerging and established hematopoietic stem cell-based gene therapy applications.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"44 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937535","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 : 2026-01-08DOI: 10.1016/j.stem.2025.12.015
Salome Stierli,Adrian Salas-Bastos,Sofia Micheli,Isabel Ballwein,Andrea Kelemen,Julia Lehmann,Benjamin Loos,Whitney Shannon Jordaan,Sebastian A Stifter,Myriam Gwerder,Ravidu Nakandalage,Janine Stadler,Melanie Greter,Lukas Sommer
Skin repair is a complex, dynamic process involving multiple cell types. Using multiplex imaging, spatial transcriptomics, and single-cell RNA sequencing, we show that peripheral nerves-containing repair glia-form a pro-reparative niche closely interacting with macrophages and proliferating fibroblasts in acute skin wounds. Repair glia function as critical early-stage regulators of wound healing by initiating the inflammatory response through secretion of monocyte chemoattractant proteins, such as CCL2, which recruit monocyte-derived macrophages. Accordingly, depletion of repair glia as well as glia-specific deletion of CCL2 reduces the number of macrophages, leading to impaired fibroblast proliferation and diminished fibroblast-to-myofibroblast transition. These findings identify repair glia as early regulators of the immune response, orchestrating the spatiotemporal progression of wound healing.
{"title":"A peripheral glial niche orchestrates the early stages of skin wound healing.","authors":"Salome Stierli,Adrian Salas-Bastos,Sofia Micheli,Isabel Ballwein,Andrea Kelemen,Julia Lehmann,Benjamin Loos,Whitney Shannon Jordaan,Sebastian A Stifter,Myriam Gwerder,Ravidu Nakandalage,Janine Stadler,Melanie Greter,Lukas Sommer","doi":"10.1016/j.stem.2025.12.015","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.015","url":null,"abstract":"Skin repair is a complex, dynamic process involving multiple cell types. Using multiplex imaging, spatial transcriptomics, and single-cell RNA sequencing, we show that peripheral nerves-containing repair glia-form a pro-reparative niche closely interacting with macrophages and proliferating fibroblasts in acute skin wounds. Repair glia function as critical early-stage regulators of wound healing by initiating the inflammatory response through secretion of monocyte chemoattractant proteins, such as CCL2, which recruit monocyte-derived macrophages. Accordingly, depletion of repair glia as well as glia-specific deletion of CCL2 reduces the number of macrophages, leading to impaired fibroblast proliferation and diminished fibroblast-to-myofibroblast transition. These findings identify repair glia as early regulators of the immune response, orchestrating the spatiotemporal progression of wound healing.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"86 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937747","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 : 2026-01-08DOI: 10.1016/j.stem.2025.12.009
Da Wang,Yufan Zhang,Yan Liu
Human pineal development and neuroendocrine regulation remain incompletely understood at the molecular and functional levels. Kiral et al.1 establish human pineal gland organoids (hPGOs) that recapitulate pinealocyte maturation, noradrenergic responsiveness, and melatonin synthesis, providing a platform for investigating circadian dysfunction and disease-associated sleep disturbances.
{"title":"Pineal gland organoids illuminate human melatonin and circadian regulation.","authors":"Da Wang,Yufan Zhang,Yan Liu","doi":"10.1016/j.stem.2025.12.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.009","url":null,"abstract":"Human pineal development and neuroendocrine regulation remain incompletely understood at the molecular and functional levels. Kiral et al.1 establish human pineal gland organoids (hPGOs) that recapitulate pinealocyte maturation, noradrenergic responsiveness, and melatonin synthesis, providing a platform for investigating circadian dysfunction and disease-associated sleep disturbances.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"47 1","pages":"4-6"},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937750","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 : 2026-01-08DOI: 10.1016/j.stem.2025.12.012
Junsung Nam,Roy Simamora,Fikri Birey
Liu et al.1 generate human sympathetic ganglion organoids and assemble them with heart-forming organoids to build functionally connected sympathetic-cardiac organoids in vitro. Their platform captures autonomic development, neuromodulation of heart function, and metabolic injury, opening new opportunities to study human autonomic disorders and cardiometabolic disease.2.
Liu et al.1生成人类交感神经节类器官，并将其与形成心脏的类器官组装在一起，在体外构建功能连接的交感-心脏类器官。他们的平台捕获了自主神经发育、心功能的神经调节和代谢损伤，为研究人类自主神经疾病和心脏代谢疾病开辟了新的机会。
{"title":"Reverse engineering the beat: Assembloid modeling of sympathetic control of the heart.","authors":"Junsung Nam,Roy Simamora,Fikri Birey","doi":"10.1016/j.stem.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.012","url":null,"abstract":"Liu et al.1 generate human sympathetic ganglion organoids and assemble them with heart-forming organoids to build functionally connected sympathetic-cardiac organoids in vitro. Their platform captures autonomic development, neuromodulation of heart function, and metabolic injury, opening new opportunities to study human autonomic disorders and cardiometabolic disease.2.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"29 1","pages":"1-3"},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937752","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 : 2026-01-08DOI: 10.1016/j.stem.2025.12.011
Monika Haoui,Pradeep Reddy,Juan Carlos Izpisua Belmonte
Aging is characterized by a progressive decline in physiological function, driven by interconnected molecular hallmarks that increase the risk of chronic diseases. To extend health span, interventions targeting these hallmarks, including lifestyle modifications, pharmacological agents, and genetic strategies, have been developed. Among these, partial reprogramming, the transient expression of Yamanaka factors, has emerged as a powerful approach to reverse age-related cellular damage and restore youthful epigenetic and transcriptional signatures without erasing cell identity. This perspective highlights the therapeutic possibilities arising from the convergence of partial reprogramming with the innovative technology of ex vivo machine perfusion. These platforms offer a unique opportunity to apply rejuvenation therapies directly to suboptimal donor organs outside the body before transplantation. Combining these strategies could significantly improve organ quality, expand the donor pool, enhance transplantation outcomes, and advance regenerative medicine.
{"title":"Anti-aging strategies and ex vivo organ rejuvenation.","authors":"Monika Haoui,Pradeep Reddy,Juan Carlos Izpisua Belmonte","doi":"10.1016/j.stem.2025.12.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.011","url":null,"abstract":"Aging is characterized by a progressive decline in physiological function, driven by interconnected molecular hallmarks that increase the risk of chronic diseases. To extend health span, interventions targeting these hallmarks, including lifestyle modifications, pharmacological agents, and genetic strategies, have been developed. Among these, partial reprogramming, the transient expression of Yamanaka factors, has emerged as a powerful approach to reverse age-related cellular damage and restore youthful epigenetic and transcriptional signatures without erasing cell identity. This perspective highlights the therapeutic possibilities arising from the convergence of partial reprogramming with the innovative technology of ex vivo machine perfusion. These platforms offer a unique opportunity to apply rejuvenation therapies directly to suboptimal donor organs outside the body before transplantation. Combining these strategies could significantly improve organ quality, expand the donor pool, enhance transplantation outcomes, and advance regenerative medicine.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"49 1","pages":"13-28"},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937754","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 : 2026-01-03DOI: 10.1016/j.stem.2025.12.019
Nathalie Saurat, Andrew P. Minotti, Maliha T. Rahman, Trisha Sikder, Chao Zhang, Daniela Cornacchia, Johannes Jungverdorben, Gabriele Ciceri, Doron Betel, Lorenz Studer
{"title":"Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration","authors":"Nathalie Saurat, Andrew P. Minotti, Maliha T. Rahman, Trisha Sikder, Chao Zhang, Daniela Cornacchia, Johannes Jungverdorben, Gabriele Ciceri, Doron Betel, Lorenz Studer","doi":"10.1016/j.stem.2025.12.019","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.019","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"24 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894478","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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