Pub Date : 2026-01-27DOI: 10.1016/j.stem.2026.01.001
Dilem Ceren Apaydin, Gaurav Sadhnani, Tiffany Carlaw, Jan Renziehausen, Elena Lizunova, Viviane Filor, Anna Hiller, Sophia Brumhard, Vincent Halim, Ulrike Brüning, Johannes Bischof, Rafaela Horbach Marodin, Daniel Z. Kurek, Manuel Rhiel, Sandra Ammann, Tatjana I. Cornu, Toni Cathomen, Leif Erik Sander, Benedikt Obermayer, Fabian Coscia, Sarah Hedtrich
Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients’ quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.
{"title":"Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models","authors":"Dilem Ceren Apaydin, Gaurav Sadhnani, Tiffany Carlaw, Jan Renziehausen, Elena Lizunova, Viviane Filor, Anna Hiller, Sophia Brumhard, Vincent Halim, Ulrike Brüning, Johannes Bischof, Rafaela Horbach Marodin, Daniel Z. Kurek, Manuel Rhiel, Sandra Ammann, Tatjana I. Cornu, Toni Cathomen, Leif Erik Sander, Benedikt Obermayer, Fabian Coscia, Sarah Hedtrich","doi":"10.1016/j.stem.2026.01.001","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.001","url":null,"abstract":"Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients’ quality of life and lack any effective treatment options. Here, we report clinically relevant <em>in situ</em> correction of the most common ARCI-causing mutation, <em>TGM1</em> c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of <em>in situ</em> gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"3 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057100","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 : 2026-01-21DOI: 10.1016/j.stem.2025.12.023
Rashmiparvathi Keshara, Karolina Kuodyte, Antje Janosch, Cordula Andree, Marc Bickle, Martin Stöter, Rico Barsacchi, Yung Hae Kim, Anne Grapin-Botton
Organoids derived from pluripotent stem cells have emerged as powerful models to study human development. To investigate signaling pathways regulating human pancreas differentiation and morphogenesis, we developed a high-content, image-based screen and quantitative multivariate analysis pipelines robust to heterogeneity to extract single-cell and organoid features using pancreatic progenitor organoids. Here, we identified 54 compounds affecting cell identity and/or morphological landscape. Focusing on one family of compounds, we found that glycogen synthase kinase 3α/β (GSK3A/B) inhibition via wingless/int-1 (WNT) signaling has a reversible effect on cell identity, repressing pancreatic progenitor markers and inducing a poised state in progenitors transitioning to acinar cells. We show that additional fibroblast growth factor (FGF) repression enables further differentiation of acinar cells, recapitulating pancreatic acinar morphogenesis and function. The ability to produce acinar cells is valuable for future studies on pancreatic exocrine function and cancer initiation in humans, as acinar cells are thought to be an important cell of origin for pancreatic adenocarcinoma.
{"title":"High-content screening of organoids reveals the mechanisms of human pancreas acinar specification","authors":"Rashmiparvathi Keshara, Karolina Kuodyte, Antje Janosch, Cordula Andree, Marc Bickle, Martin Stöter, Rico Barsacchi, Yung Hae Kim, Anne Grapin-Botton","doi":"10.1016/j.stem.2025.12.023","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.023","url":null,"abstract":"Organoids derived from pluripotent stem cells have emerged as powerful models to study human development. To investigate signaling pathways regulating human pancreas differentiation and morphogenesis, we developed a high-content, image-based screen and quantitative multivariate analysis pipelines robust to heterogeneity to extract single-cell and organoid features using pancreatic progenitor organoids. Here, we identified 54 compounds affecting cell identity and/or morphological landscape. Focusing on one family of compounds, we found that glycogen synthase kinase 3α/β (GSK3A/B) inhibition via wingless/int-1 (WNT) signaling has a reversible effect on cell identity, repressing pancreatic progenitor markers and inducing a poised state in progenitors transitioning to acinar cells. We show that additional fibroblast growth factor (FGF) repression enables further differentiation of acinar cells, recapitulating pancreatic acinar morphogenesis and function. The ability to produce acinar cells is valuable for future studies on pancreatic exocrine function and cancer initiation in humans, as acinar cells are thought to be an important cell of origin for pancreatic adenocarcinoma.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"69 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005601","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 : 2026-01-20DOI: 10.1016/j.stem.2025.12.022
Donald E. Ingber
{"title":"Challenges and opportunities for human Organ Chips in FDA assessments and pharma pipelines,","authors":"Donald E. Ingber","doi":"10.1016/j.stem.2025.12.022","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.022","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014811","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 : 2026-01-13DOI: 10.1016/j.stem.2025.12.020
Bruna Paulsen, Ferran Barrachina, Sabrina Piechota, Alexander D. Noblett, Mark Johnson, Simone Kats, Cassandra Lew, Maria Marchante, Alexandra B. Figueroa, Itzel Garcia Granada, Elizabeth Ingalls Lopez, Erick Martinez, Paula Ricra, Camila Carlos, Jazmin Meza, Wendy Montanchez, Pilar Pino, Cesar Reategui, Enrique Noriega, Alicia Elias, Luis Noriega-Portella, Gus Haddad, Dina Radenkovic, Eugenia Moran, Pamela Villanueva, Jose Guiterrez, Luis Guzman, Pietro Bortolleto, David F. Albertini, Michel De Vos, Christian C. Kramme
{"title":"Development of human induced pluripotent stem cell-derived ovarian support cells as a clinical-grade product for in vitro fertilization","authors":"Bruna Paulsen, Ferran Barrachina, Sabrina Piechota, Alexander D. Noblett, Mark Johnson, Simone Kats, Cassandra Lew, Maria Marchante, Alexandra B. Figueroa, Itzel Garcia Granada, Elizabeth Ingalls Lopez, Erick Martinez, Paula Ricra, Camila Carlos, Jazmin Meza, Wendy Montanchez, Pilar Pino, Cesar Reategui, Enrique Noriega, Alicia Elias, Luis Noriega-Portella, Gus Haddad, Dina Radenkovic, Eugenia Moran, Pamela Villanueva, Jose Guiterrez, Luis Guzman, Pietro Bortolleto, David F. Albertini, Michel De Vos, Christian C. Kramme","doi":"10.1016/j.stem.2025.12.020","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.020","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"265 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962526","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 : 2026-01-12DOI: 10.1016/j.stem.2025.12.013
Kritika Sharma,Rouhollah Habibey,Mariana M Ribeiro,Bohao Cui,Rebecca A Siwicki,Johannes Striebel,Julia S Pawlick,Jasmin Zorn,Larissa Utz,Magdalena Renner,Simone Picelli,Frank G Holz,Carmen Ruiz de Almodóvar,Cameron S Cowan,Volker Busskamp
Retinal organoids are widely used to model human retinal development and disease, but their utility is limited by the absence of vascular networks and stable axonal projections, which contribute to retinal ganglion cell degeneration and loss of function. To address these challenges, we incorporated stem cell-derived endothelial cells to induce transient vascular-like networks and used microfluidic devices to stabilize axonal growth. The resulting organoids showed reduced hypoxia, increased size, and decreased apoptosis, indicating improved long-term survival and maturation of retinal ganglion cells. Integration with microfluidic-microelectrode arrays enabled stable recordings of spontaneous and optogenetically evoked activity, which persisted beyond the time when control organoids lost function. At later stages, these transiently vascularized organoids displayed photoreceptor-driven ON, OFF, and ON-OFF light responses, indicating circuit-level retinal activity. This bioengineered platform establishes a long-term, functional model of the human retina as a transformative tool for retinal research and therapeutic innovation.
{"title":"Retinal ganglion cell survival and functional maturation in transiently vascularized human retinal organoids.","authors":"Kritika Sharma,Rouhollah Habibey,Mariana M Ribeiro,Bohao Cui,Rebecca A Siwicki,Johannes Striebel,Julia S Pawlick,Jasmin Zorn,Larissa Utz,Magdalena Renner,Simone Picelli,Frank G Holz,Carmen Ruiz de Almodóvar,Cameron S Cowan,Volker Busskamp","doi":"10.1016/j.stem.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.013","url":null,"abstract":"Retinal organoids are widely used to model human retinal development and disease, but their utility is limited by the absence of vascular networks and stable axonal projections, which contribute to retinal ganglion cell degeneration and loss of function. To address these challenges, we incorporated stem cell-derived endothelial cells to induce transient vascular-like networks and used microfluidic devices to stabilize axonal growth. The resulting organoids showed reduced hypoxia, increased size, and decreased apoptosis, indicating improved long-term survival and maturation of retinal ganglion cells. Integration with microfluidic-microelectrode arrays enabled stable recordings of spontaneous and optogenetically evoked activity, which persisted beyond the time when control organoids lost function. At later stages, these transiently vascularized organoids displayed photoreceptor-driven ON, OFF, and ON-OFF light responses, indicating circuit-level retinal activity. This bioengineered platform establishes a long-term, functional model of the human retina as a transformative tool for retinal research and therapeutic innovation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"12 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961381","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.2025.12.017
Zahir Shah,Lei Tian,Michael A Caligiuri,Dan S Kaufman,Jianhua Yu
Allogeneic cell-based therapies hold great promise for cancer immunotherapy but face challenges like scalability, immune rejection, graft-versus-host disease, and toxicities. Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells (iPSCs), offer a scalable and adaptable platform to address these limitations. hPSCs provide an inexhaustible source of immune cells that can be genetically modified at the single-cell level to enhance anti-tumor activity and reduce immunogenicity. Recent advancements in generating iPSC-derived natural killer (NK) cells, T cells, and macrophages are opening the door to safer and more effective immunotherapies. This review examines the progress, challenges, and future directions in utilizing hPSC-derived immune cells to enhance cancer treatment and overcome barriers in allogeneic therapy.
{"title":"Human pluripotent stem cell-derived innate and adaptive immune cells for cancer immunotherapy.","authors":"Zahir Shah,Lei Tian,Michael A Caligiuri,Dan S Kaufman,Jianhua Yu","doi":"10.1016/j.stem.2025.12.017","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.017","url":null,"abstract":"Allogeneic cell-based therapies hold great promise for cancer immunotherapy but face challenges like scalability, immune rejection, graft-versus-host disease, and toxicities. Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells (iPSCs), offer a scalable and adaptable platform to address these limitations. hPSCs provide an inexhaustible source of immune cells that can be genetically modified at the single-cell level to enhance anti-tumor activity and reduce immunogenicity. Recent advancements in generating iPSC-derived natural killer (NK) cells, T cells, and macrophages are opening the door to safer and more effective immunotherapies. This review examines the progress, challenges, and future directions in utilizing hPSC-derived immune cells to enhance cancer treatment and overcome barriers in allogeneic therapy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937748","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.2025.12.014
Sarah Stanley
Editors' note: The Ogawa-Yamanaka Stem Cell Prize recognizes groundbreaking work in translational regenerative medicine using reprogrammed cells. The prize is supported by Gladstone Institutes, in partnership with Cell Press. Among his myriad accomplishments, Rudolf Jaenisch-winner of the 2025 Ogawa-Yamanaka Stem Cell Prize-was the first to demonstrate the potential of induced pluripotent stem cells to treat disease.
{"title":"A sculptor of modern regenerative medicine.","authors":"Sarah Stanley","doi":"10.1016/j.stem.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.014","url":null,"abstract":"Editors' note: The Ogawa-Yamanaka Stem Cell Prize recognizes groundbreaking work in translational regenerative medicine using reprogrammed cells. The prize is supported by Gladstone Institutes, in partnership with Cell Press. Among his myriad accomplishments, Rudolf Jaenisch-winner of the 2025 Ogawa-Yamanaka Stem Cell Prize-was the first to demonstrate the potential of induced pluripotent stem cells to treat disease.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"3 1","pages":"10-12"},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937749","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.2025.12.008
Zhifu Wang,Danyi Zheng,Shu-Min Chou,Phil Jun Kang,Fei Ye,Su-Chun Zhang
Neural transplantation holds the potential to repair damaged neural circuits in neurological diseases. However, it remains unknown how the grafted neurons project axons to and make functional connections with the appropriate targets to repair the damaged circuit at the adult stage. Here, we report that human cortical progenitors, transplanted into the ischemic mouse motor cortex, matured and integrated into cortical and subcortical neural circuits, including the corticospinal tract. Neuronal tracing combined with single-nuclei RNA sequencing revealed the close relationship between the transcription profiles of a cortical neuronal subtype, especially those of axon guidance and synapse assembly, with the specific target projection and synapse organization. Machine learning-based regression further identified the transcriptional codes for the targeted projection and circuit integration to reconstruct the damaged circuits. Our finding opens a promising strategy for treating neurological diseases through promoting regeneration and neural transplantation.
{"title":"Transcriptional code for circuit integration in the injured brain by transplanted human neurons.","authors":"Zhifu Wang,Danyi Zheng,Shu-Min Chou,Phil Jun Kang,Fei Ye,Su-Chun Zhang","doi":"10.1016/j.stem.2025.12.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.008","url":null,"abstract":"Neural transplantation holds the potential to repair damaged neural circuits in neurological diseases. However, it remains unknown how the grafted neurons project axons to and make functional connections with the appropriate targets to repair the damaged circuit at the adult stage. Here, we report that human cortical progenitors, transplanted into the ischemic mouse motor cortex, matured and integrated into cortical and subcortical neural circuits, including the corticospinal tract. Neuronal tracing combined with single-nuclei RNA sequencing revealed the close relationship between the transcription profiles of a cortical neuronal subtype, especially those of axon guidance and synapse assembly, with the specific target projection and synapse organization. Machine learning-based regression further identified the transcriptional codes for the targeted projection and circuit integration to reconstruct the damaged circuits. Our finding opens a promising strategy for treating neurological diseases through promoting regeneration and neural transplantation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"397 1","pages":"44-57.e7"},"PeriodicalIF":23.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937751","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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