Cell stem cellPub Date : 2025-05-01DOI: 10.1016/j.stem.2025.04.004
Timothy Chai, Julie Y. Chen, Kyle M. Loh
{"title":"Dopaminergic neurons entering the brain under the immunological cover of darkness","authors":"Timothy Chai, Julie Y. Chen, Kyle M. Loh","doi":"10.1016/j.stem.2025.04.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.004","url":null,"abstract":"The ability to transplant immunologically foreign cells into an animal without immune suppression would be transformative. Pavan et al. show that human pluripotent stem cell-derived dopaminergic neuron progenitors engineered to express eight immune-evasive proteins can engraft in humanized mice and a rat model of Parkinson’s disease without recourse to immune suppression.<span><span><sup>1</sup></span></span>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"68 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893295","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}
{"title":"Bioengineering innovations for neural organoids with enhanced fidelity and function","authors":"Yubing Sun, Yoshiho Ikeuchi, Feng Guo, Insoo Hyun, Guo-li Ming, Jianping Fu","doi":"10.1016/j.stem.2025.03.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.014","url":null,"abstract":"Neural organoids have been utilized to recapitulate different aspects of the developing nervous system. While hailed as promising experimental tools for studying human neural development and neuropathology, current neural organoids do not fully recapitulate the anatomy or microcircuitry-level functionality of the developing brain, spinal cord, or peripheral nervous system. In this review, we discuss emerging bioengineering approaches that control morphogen signals and biophysical microenvironments, which have improved the efficiency, fidelity, and utility of neural organoids. Furthermore, advancements in bioengineered tools have facilitated more sophisticated analyses of neural organoid functions and applications, including improved neural-bioelectronic interfaces and organoid-based information processing. Emerging bioethical issues associated with advanced neural organoids are also discussed. Future opportunities of neural organoid research lie in enhancing their fidelity, maturity, and complexity and expanding their applications in a scalable manner.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"45 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893301","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}
Cell stem cellPub Date : 2025-05-01DOI: 10.1016/j.stem.2025.04.005
María J. Rodríguez Colman, Katharina F. Sonnen
{"title":"Signaling switches: Metabolism regulates gastruloid self-organization","authors":"María J. Rodríguez Colman, Katharina F. Sonnen","doi":"10.1016/j.stem.2025.04.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.005","url":null,"abstract":"Metabolic regulation of embryonic development is increasingly recognized. Villaronga-Luque et al.<span><span><sup>1</sup></span></span> and Stopornwongkul et al.<span><span><sup>2</sup></span></span> show that metabolic activity influences gastruloid formation from mouse embryonic stem cells, revealing that the balance between glycolysis and oxidative phosphorylation regulates cell fate decisions during gastruloid self-organization.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"20 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893293","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}
Cell stem cellPub Date : 2025-05-01DOI: 10.1016/j.stem.2025.04.001
Branden Lee, Noah Brookes, Adam S. Levin
{"title":"Litigation of unlicensed US stem cell products","authors":"Branden Lee, Noah Brookes, Adam S. Levin","doi":"10.1016/j.stem.2025.04.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.001","url":null,"abstract":"Financial dispositions against unapproved stem cell interventions have grown significantly, with successful class-action lawsuits, malpractice claims, and collaborative prosecutions between government agencies. In addition to improved dispositions, federal circuit courts have given unanimous affirmation to the FDA’s regulatory authority over stem cell interventions, establishing critical precedents for oversight.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"91 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893297","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}
Cell stem cellPub Date : 2025-05-01DOI: 10.1016/j.stem.2025.04.002
Jane Reznick, Carien M. Niessen
{"title":"IRF6 hits the sweet spot","authors":"Jane Reznick, Carien M. Niessen","doi":"10.1016/j.stem.2025.04.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.002","url":null,"abstract":"Glucose serves as an essential energy source for cells. In this issue, Lopez-Pajares et al.<span><span><sup>1</sup></span></span> uncover a role for glucose uncoupled from its energetic function. During epidermal differentiation, free glucose accumulates and binds the pro-differentiation transcription factor IRF6, promoting its dimerization and DNA binding to activate genes that drive differentiation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"24 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893291","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}
Cell stem cellPub Date : 2025-04-29DOI: 10.1016/j.stem.2025.04.009
Sergei Doulatov, Linda T. Vo, Stephanie S. Chou, Peter G. Kim, Natasha Arora, Hu Li, Brandon K. Hadland, Irwin D. Bernstein, James J. Collins, Leonard I. Zon, George Q. Daley
{"title":"Induction of Multipotential Hematopoietic Progenitors from Human Pluripotent Stem Cells via Respecification of Lineage-Restricted Precursors","authors":"Sergei Doulatov, Linda T. Vo, Stephanie S. Chou, Peter G. Kim, Natasha Arora, Hu Li, Brandon K. Hadland, Irwin D. Bernstein, James J. Collins, Leonard I. Zon, George Q. Daley","doi":"10.1016/j.stem.2025.04.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.009","url":null,"abstract":"(Cell Stem Cell <em>13</em>, 459–470; October 3, 2013)","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"68 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885266","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}
Cell stem cellPub Date : 2025-04-16DOI: 10.1016/j.stem.2025.03.011
Kristina S. Stapornwongkul, Elisa Hahn, Patryk Poliński, Laura Salamó Palau, Krisztina Arató, LiAng Yao, Kate Williamson, Nicola Gritti, Kerim Anlas, Mireia Osuna Lopez, Kiran R. Patil, Idse Heemskerk, Miki Ebisuya, Vikas Trivedi
{"title":"Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling","authors":"Kristina S. Stapornwongkul, Elisa Hahn, Patryk Poliński, Laura Salamó Palau, Krisztina Arató, LiAng Yao, Kate Williamson, Nicola Gritti, Kerim Anlas, Mireia Osuna Lopez, Kiran R. Patil, Idse Heemskerk, Miki Ebisuya, Vikas Trivedi","doi":"10.1016/j.stem.2025.03.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.011","url":null,"abstract":"Metabolic pathways can influence cell fate decisions, yet their regulative role during embryonic development remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in regulating signaling pathways involved in mesoderm and endoderm specification. Using a mouse embryonic stem cell (mESC)-based <em>in vitro</em> model for gastrulation, we found that glycolysis inhibition increases ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. We further show that glycolysis acts as an upstream regulator of Nodal and Wnt signaling and that its influence on cell fate specification can be decoupled from its effects on growth. Finally, we confirm the generality of our findings using a human gastrulation model. Our work underscores the dependence of signaling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision-making.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"47 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837079","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}
Cell stem cellPub Date : 2025-04-16DOI: 10.1016/j.stem.2025.03.012
Alba Villaronga-Luque, Ryan G. Savill, Natalia López-Anguita, Adriano Bolondi, Sumit Garai, Seher Ipek Gassaloglu, Roua Rouatbi, Kathrin Schmeisser, Aayush Poddar, Lisa Bauer, Tiago Alves, Sofia Traikov, Jonathan Rodenfels, Triantafyllos Chavakis, Aydan Bulut-Karslioglu, Jesse V. Veenvliet
{"title":"Integrated molecular-phenotypic profiling reveals metabolic control of morphological variation in a stem-cell-based embryo model","authors":"Alba Villaronga-Luque, Ryan G. Savill, Natalia López-Anguita, Adriano Bolondi, Sumit Garai, Seher Ipek Gassaloglu, Roua Rouatbi, Kathrin Schmeisser, Aayush Poddar, Lisa Bauer, Tiago Alves, Sofia Traikov, Jonathan Rodenfels, Triantafyllos Chavakis, Aydan Bulut-Karslioglu, Jesse V. Veenvliet","doi":"10.1016/j.stem.2025.03.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.012","url":null,"abstract":"Considerable phenotypic variation under identical culture conditions limits the potential of stem-cell-based embryo models (SEMs) in basic and applied research. The biological processes causing this seemingly stochastic variation remain unclear. Here, we investigated the roots of phenotypic variation by parallel recording of transcriptomic states and morphological history in individual structures modeling embryonic trunk formation. Machine learning and integration of time-resolved single-cell RNA sequencing with imaging-based phenotypic profiling identified early features predictive of phenotypic end states. Leveraging this predictive power revealed that early imbalance of oxidative phosphorylation and glycolysis results in aberrant morphology and a neural lineage bias, which we confirmed by metabolic measurements. Accordingly, metabolic interventions improved phenotypic end states. Collectively, our work establishes divergent metabolic states as drivers of phenotypic variation and offers a broadly applicable framework to chart and predict phenotypic variation in organoids and SEMs. The strategy can be used to identify and control underlying biological processes, ultimately increasing reproducibility.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837080","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}
Cell stem cellPub Date : 2025-04-14DOI: 10.1016/j.stem.2025.03.009
Jean Paul Chadarevian, Hayk Davtyan, Alina L. Chadarevian, Jasmine Nguyen, Joia K. Capocchi, Lauren Le, Adrian Escobar, Talar Chadarevian, Kimiya Mansour, Ekaterina Deynega, Michael Mgerian, Christina Tu, Sepideh Kiani Shabestari, William Carlen-Jones, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Robert C. Spitale, Mathew Blurton-Jones
{"title":"Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins","authors":"Jean Paul Chadarevian, Hayk Davtyan, Alina L. Chadarevian, Jasmine Nguyen, Joia K. Capocchi, Lauren Le, Adrian Escobar, Talar Chadarevian, Kimiya Mansour, Ekaterina Deynega, Michael Mgerian, Christina Tu, Sepideh Kiani Shabestari, William Carlen-Jones, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Robert C. Spitale, Mathew Blurton-Jones","doi":"10.1016/j.stem.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.009","url":null,"abstract":"Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer’s disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"42 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827152","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}