Pub Date : 2025-01-17DOI: 10.1016/j.stem.2024.12.006
Bing Peng, Qingyi Wang, Feixiang Zhang, Hui Shen, Peng Du
Embryo development begins with zygotic genome activation (ZGA), eventually generating blastocysts for implantation. However, in vitro systems modeling the pre-implantation development are still absent and challenging. Here, we used mouse totipotent blastomere-like cells (TBLCs) to develop spontaneous differentiation and blastoid formation systems, respectively. We found Wnt signaling enabled the rapid expansion of TBLCs and the optimization of their culture medium. We successfully developed a TBLC-spontaneous differentiation system in which mouse TBLCs (mTBLCs) firstly converted into two types of ZGA-like cells (ZLCs) distinguished by Zscan4 expression. Surprisingly, Zscan4-, but not Zscan4+, ZLCs further passed through intermediate 4-cell and then 8-cell/morula stages to produce epiblast, primitive endoderm, and trophectoderm lineages. Significantly, single TBLCs underwent expansion, compaction, and polarization to efficiently generate blastocyst-like structures and even post-implantation egg-cylinder-like structures. Conclusively, we established TBLC-based differentiation and embryo-like structure formation systems to model early embryonic development, offering criteria for evaluating and understanding totipotency.
{"title":"Mouse totipotent blastomere-like cells model embryogenesis from zygotic genome activation to post implantation","authors":"Bing Peng, Qingyi Wang, Feixiang Zhang, Hui Shen, Peng Du","doi":"10.1016/j.stem.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.006","url":null,"abstract":"Embryo development begins with zygotic genome activation (ZGA), eventually generating blastocysts for implantation. However, <em>in vitro</em> systems modeling the pre-implantation development are still absent and challenging. Here, we used mouse totipotent blastomere-like cells (TBLCs) to develop spontaneous differentiation and blastoid formation systems, respectively. We found Wnt signaling enabled the rapid expansion of TBLCs and the optimization of their culture medium. We successfully developed a TBLC-spontaneous differentiation system in which mouse TBLCs (mTBLCs) firstly converted into two types of ZGA-like cells (ZLCs) distinguished by Zscan4 expression. Surprisingly, Zscan4-, but not Zscan4+, ZLCs further passed through intermediate 4-cell and then 8-cell/morula stages to produce epiblast, primitive endoderm, and trophectoderm lineages. Significantly, single TBLCs underwent expansion, compaction, and polarization to efficiently generate blastocyst-like structures and even post-implantation egg-cylinder-like structures. Conclusively, we established TBLC-based differentiation and embryo-like structure formation systems to model early embryonic development, offering criteria for evaluating and understanding totipotency.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"27 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987693","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 : 2025-01-15DOI: 10.1016/j.stem.2024.12.008
Ran Jing, Marcelo Falchetti, Tianxiao Han, Mohamad Najia, Luca T. Hensch, Eleanor Meader, Edroaldo Lummertz da Rocha, Martin Kononov, Stephanie Wang, Trevor Bingham, Zhiheng Li, Yunliang Zhao, Katie Frenis, Caroline Kubaczka, Song Yang, Deepak Jha, Gabriela F. Rodrigues-Luiz, R. Grant Rowe, Thorsten M. Schlaeger, Marcela V. Maus, George Q. Daley
(Cell Stem Cell 32, 71–85; January 2, 2025)
(细胞干细胞32,71-85；2025年1月2日)
{"title":"Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP","authors":"Ran Jing, Marcelo Falchetti, Tianxiao Han, Mohamad Najia, Luca T. Hensch, Eleanor Meader, Edroaldo Lummertz da Rocha, Martin Kononov, Stephanie Wang, Trevor Bingham, Zhiheng Li, Yunliang Zhao, Katie Frenis, Caroline Kubaczka, Song Yang, Deepak Jha, Gabriela F. Rodrigues-Luiz, R. Grant Rowe, Thorsten M. Schlaeger, Marcela V. Maus, George Q. Daley","doi":"10.1016/j.stem.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.008","url":null,"abstract":"(Cell Stem Cell <em>32</em>, 71–85; January 2, 2025)","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"27 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987032","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 : 2025-01-15DOI: 10.1016/j.stem.2024.12.002
Terren K. Niethamer, Joseph D. Planer, Michael P. Morley, Apoorva Babu, Gan Zhao, Maria C. Basil, Edward Cantu, David B. Frank, Joshua M. Diamond, Ana N. Nottingham, Shanru Li, Arnav Sharma, Hannah Hallquist, Lillian I. Levin, Su Zhou, Andrew E. Vaughan, Edward E. Morrisey
Functional regeneration of the lung’s gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using single-cell transcriptomics combined with lineage tracing of proliferating progenitors, we examined mouse lung regeneration after influenza injury, demonstrating an asynchronously phased response across different cellular compartments. This longitudinal atlas of injury responses has produced a catalog of transient and persistent transcriptional alterations in cells as they transit across axes of differentiation. These cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares hallmarks with developing lung endothelium and endothelial aberrations found in degenerative human lung diseases. This dataset provides a foundational resource to understand the complexity of cellular and molecular responses to injury and correlations to responses found in human development and disease.
{"title":"Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states","authors":"Terren K. Niethamer, Joseph D. Planer, Michael P. Morley, Apoorva Babu, Gan Zhao, Maria C. Basil, Edward Cantu, David B. Frank, Joshua M. Diamond, Ana N. Nottingham, Shanru Li, Arnav Sharma, Hannah Hallquist, Lillian I. Levin, Su Zhou, Andrew E. Vaughan, Edward E. Morrisey","doi":"10.1016/j.stem.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.002","url":null,"abstract":"Functional regeneration of the lung’s gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using single-cell transcriptomics combined with lineage tracing of proliferating progenitors, we examined mouse lung regeneration after influenza injury, demonstrating an asynchronously phased response across different cellular compartments. This longitudinal atlas of injury responses has produced a catalog of transient and persistent transcriptional alterations in cells as they transit across axes of differentiation. These cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares hallmarks with developing lung endothelium and endothelial aberrations found in degenerative human lung diseases. This dataset provides a foundational resource to understand the complexity of cellular and molecular responses to injury and correlations to responses found in human development and disease.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"7 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981688","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 : 2025-01-14DOI: 10.1016/j.stem.2024.12.010
Han Xie, Chenrui An, Bing Bai, Jiajia Luo, Nianqin Sun, Baiquan Ci, Long Jin, Peiting Mo, Yawen Lu, Ke Zhong, Yang Yu, Tao Tan, Rong Li, Yong Fan
Blastoids are a promising model for studying early human embryogenesis, but current models have limitations in post-implantation development and lack comprehensive epigenetic assessments, especially regarding genomic imprinting. These issues can lead to failures in accurately modeling early embryonic development. In this study, we developed a high-fidelity blastoid model using 4 chemicals + leukemia inhibitory factor (LIF) (4CL) naive human pluripotent stem cells (hPSCs) (4CL blastoids). 4CL blastoids closely resemble human blastocysts in morphology and transcriptional profiles, exhibiting similar DNA methylation and gene imprinting patterns. By extending the 3D culture to 14 days, these blastoids mimic early gastrulation, demonstrating the specification and migration of cells. They also show the transcriptional signature of hemogenic angioblast (HAB) cells at Carnegie stage 6 (CS6). This model bridges pre- and post-implantation stages, offering valuable insights into early tissue formation and human development.
{"title":"Modeling early gastrulation in human blastoids with DNA methylation patterns of natural blastocysts","authors":"Han Xie, Chenrui An, Bing Bai, Jiajia Luo, Nianqin Sun, Baiquan Ci, Long Jin, Peiting Mo, Yawen Lu, Ke Zhong, Yang Yu, Tao Tan, Rong Li, Yong Fan","doi":"10.1016/j.stem.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.010","url":null,"abstract":"Blastoids are a promising model for studying early human embryogenesis, but current models have limitations in post-implantation development and lack comprehensive epigenetic assessments, especially regarding genomic imprinting. These issues can lead to failures in accurately modeling early embryonic development. In this study, we developed a high-fidelity blastoid model using 4 chemicals + leukemia inhibitory factor (LIF) (4CL) naive human pluripotent stem cells (hPSCs) (4CL blastoids). 4CL blastoids closely resemble human blastocysts in morphology and transcriptional profiles, exhibiting similar DNA methylation and gene imprinting patterns. By extending the 3D culture to 14 days, these blastoids mimic early gastrulation, demonstrating the specification and migration of cells. They also show the transcriptional signature of hemogenic angioblast (HAB) cells at Carnegie stage 6 (CS6). This model bridges pre- and post-implantation stages, offering valuable insights into early tissue formation and human development.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"75 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974573","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 : 2025-01-08DOI: 10.1016/j.stem.2024.12.007
Georgia Lea, Paula Doria-Borrell, Ana Ferrero-Micó, Anakha Varma, Claire Simon, Holly Anderson, Laura Biggins, Katrien De Clercq, Simon Andrews, Kathy K. Niakan, Lenka Gahurova, Naomi McGovern, Vicente Pérez-García, Courtney W. Hanna
The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental “methylome” is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1st trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of DNMT3L expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in de novo methylation in trophoblast development in human embryogenesis.
{"title":"Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome","authors":"Georgia Lea, Paula Doria-Borrell, Ana Ferrero-Micó, Anakha Varma, Claire Simon, Holly Anderson, Laura Biggins, Katrien De Clercq, Simon Andrews, Kathy K. Niakan, Lenka Gahurova, Naomi McGovern, Vicente Pérez-García, Courtney W. Hanna","doi":"10.1016/j.stem.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.007","url":null,"abstract":"The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental “methylome” is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1<sup>st</sup> trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of <em>DNMT3L</em> expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in <em>de novo</em> methylation in trophoblast development in human embryogenesis.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"2 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936108","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 : 2025-01-02DOI: 10.1016/j.stem.2024.12.005
Agnete Kirkeby, Heather Main, Melissa Carpenter
Since the first derivation of human pluripotent stem cells (hPSCs) 27 years ago, technologies to control their differentiation and manufacturing have advanced immensely, enabling increasing numbers of clinical trials with hPSC-derived products. Here, we revew the landscape of interventional hPSC trials worldwide, highlighting available data on clinical safety and efficacy. As of December 2024, we identify 116 clinical trials with regulatory approval, testing 83 hPSC products. The majority of trials are targeting eye, central nervous system, and cancer. To date, more than 1,200 patients have been dosed with hPSC products, accumulating to >1011 clinically administered cells, so far showing no generalizable safety concerns.
{"title":"Pluripotent stem-cell-derived therapies in clinical trial: A 2025 update","authors":"Agnete Kirkeby, Heather Main, Melissa Carpenter","doi":"10.1016/j.stem.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.005","url":null,"abstract":"Since the first derivation of human pluripotent stem cells (hPSCs) 27 years ago, technologies to control their differentiation and manufacturing have advanced immensely, enabling increasing numbers of clinical trials with hPSC-derived products. Here, we revew the landscape of interventional hPSC trials worldwide, highlighting available data on clinical safety and efficacy. As of December 2024, we identify 116 clinical trials with regulatory approval, testing 83 hPSC products. The majority of trials are targeting eye, central nervous system, and cancer. To date, more than 1,200 patients have been dosed with hPSC products, accumulating to >10<sup>11</sup> clinically administered cells, so far showing no generalizable safety concerns.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912176","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 : 2025-01-02DOI: 10.1016/j.stem.2024.12.003
Susana Navarro, Paula Río
Diamond-Blackfan anemia syndrome is a ribosomopathy classified among the bone marrow failure syndromes. This disease exhibits significant heterogeneity, with up to 24 genetic variants identified to date. Voit et al.1 present compelling preclinical evidence supporting a universal lentiviral gene therapy strategy to treat patients, regardless of the specific gene involved.
{"title":"All-in-one gene therapy alternative for DBAS","authors":"Susana Navarro, Paula Río","doi":"10.1016/j.stem.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.003","url":null,"abstract":"Diamond-Blackfan anemia syndrome is a ribosomopathy classified among the bone marrow failure syndromes. This disease exhibits significant heterogeneity, with up to 24 genetic variants identified to date. Voit et al.<span><span><sup>1</sup></span></span> present compelling preclinical evidence supporting a universal lentiviral gene therapy strategy to treat patients, regardless of the specific gene involved.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"36 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912144","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 : 2025-01-02DOI: 10.1016/j.stem.2024.12.001
Soniya Tamhankar, Eric V. Shusta, Sean P. Palecek
Tissue-engineered vascular conduits (TEVCs) are a promising blood vessel replacement. In a recent publication in Cell Stem Cell,1 Park et al. developed TEVCs comprised of decellularized human umbilical arteries lined with shear-trained, human induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs) that resisted thrombosis and exhibited patency upon grafting into the rat inferior vena cava (IVC).
{"title":"Engineered hiPSC-derived vascular graft brings hope for thrombosis-free vascular therapy","authors":"Soniya Tamhankar, Eric V. Shusta, Sean P. Palecek","doi":"10.1016/j.stem.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.001","url":null,"abstract":"Tissue-engineered vascular conduits (TEVCs) are a promising blood vessel replacement. In a recent publication in <em>Cell Stem Cell</em>,<span><span><sup>1</sup></span></span> Park et al. developed TEVCs comprised of decellularized human umbilical arteries lined with shear-trained, human induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs) that resisted thrombosis and exhibited patency upon grafting into the rat inferior vena cava (IVC).","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"68 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912158","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 : 2025-01-02DOI: 10.1016/j.stem.2024.12.004
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. Winner of the 2024 Ogawa-Yamanaka Stem Cell Prize Rusty Gage made landmark discoveries that fundamentally shifted the field of neuroscience.
{"title":"Perceiving the brain like never before","authors":"Sarah Stanley","doi":"10.1016/j.stem.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.12.004","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. Winner of the 2024 Ogawa-Yamanaka Stem Cell Prize Rusty Gage made landmark discoveries that fundamentally shifted the field of neuroscience.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"81 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912145","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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