Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-03DOI: 10.1016/j.stemcr.2025.102471
Roni Sarel-Gallily, Keith M Gunapala, Nissim Benvenisty
{"title":"Large-scale analysis of loss of chromosome Y in human pluripotent stem cells: Implications for Turner syndrome and ribosomopathies.","authors":"Roni Sarel-Gallily, Keith M Gunapala, Nissim Benvenisty","doi":"10.1016/j.stemcr.2025.102471","DOIUrl":"10.1016/j.stemcr.2025.102471","url":null,"abstract":"<p><p>Loss of chromosome Y (LOY) occurs in aging and cancers, but its extent and implications in human embryonic stem cells (hESCs) have not been studied. Here, we analyzed over 2,650 RNA sequencing (RNA-seq) samples from hESCs and their differentiated derivatives to detect LOY. We found that 12% of hESC samples have lost their chromosome Y and identified LOY in all three germ layers. Differential expression analysis revealed that LOY samples showed a decrease in expression of pluripotency markers and in ribosomal protein (RP) genes. Strikingly, significant RP transcription downregulation was observed in most RP genes, although there is only one expressed Y-linked RP gene. We further analyzed RP expression in Turner syndrome and Diamond-Blackfan anemia samples and observed overall downregulation of RP transcription. This broad analysis sheds light on the scope and effects of LOY in hESCs, suggesting a novel dosage-sensitive mechanism regulating RP gene transcription in LOY and autosomal ribosomopathies.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102471"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-05-01DOI: 10.1016/j.stemcr.2025.102498
Matilda Beckett, Sarah Franklin, Peter J Rugg-Gunn
{"title":"Identifying enabling strategies for effective public dialogue in human embryo research.","authors":"Matilda Beckett, Sarah Franklin, Peter J Rugg-Gunn","doi":"10.1016/j.stemcr.2025.102498","DOIUrl":"10.1016/j.stemcr.2025.102498","url":null,"abstract":"<p><p>Public dialogue is crucial for understanding societal views on human embryo research, and the complexity and sensitivity of this topic require special considerations of how such dialogues are facilitated. Here, we identify enablers of effective dialogue, which can improve the design and delivery of engagement exercises related to embryo research.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102498"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-03DOI: 10.1016/j.stemcr.2025.102473
Samiyah Shafiq, Kiyofumi Hamashima, Laura A Guest, Ali H Al-Anbaki, Fabio M R Amaral, Daniel H Wiseman, Valerie Kouskoff, Georges Lacaud, Yuin-Han Loh, Kiran Batta
{"title":"Competing dynamic gene regulatory networks involved in fibroblast reprogramming to hematopoietic progenitor cells.","authors":"Samiyah Shafiq, Kiyofumi Hamashima, Laura A Guest, Ali H Al-Anbaki, Fabio M R Amaral, Daniel H Wiseman, Valerie Kouskoff, Georges Lacaud, Yuin-Han Loh, Kiran Batta","doi":"10.1016/j.stemcr.2025.102473","DOIUrl":"10.1016/j.stemcr.2025.102473","url":null,"abstract":"<p><p>Direct reprogramming of somatic cells offers a potentially safer therapeutic approach to generate patient-specific hematopoietic cells. However, this strategy is limited by stochasticity of reprogramming. Investigating the gene regulatory networks involved during reprogramming would help generate functional cells in adequate numbers. To address this, we developed an inducible system to reprogram fibroblasts to hematopoietic progenitor cells by ectopically expressing the two transcription factors SCL and LMO2. Transcriptome and epigenome analysis at different stages of reprogramming revealed uniform silencing of fibroblast genes and upregulation of the hemogenic endothelial program. Integrated analysis suggested that the transcription factors FLI1, GATA1/2, and KLF14 are direct targets of SCL/LMO2, which subsequently induce the hematopoietic program. Single-cell RNA sequencing revealed conflicting and competing fate decisions at intermediate stages of reprogramming. Inhibiting signaling pathways associated with competing neuronal fate enhanced reprogramming efficiency. In conclusion, this study identifies early/intermediate reprogramming events and associated pathways that could be targeted to improve reprogramming efficiency.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102473"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-24DOI: 10.1016/j.stemcr.2025.102480
Niamh Moriarty, Tyra D Fraser, Cameron P J Hunt, Georgia Eleftheriou, Jessica A Kauhausen, Lachlan H Thompson, Clare L Parish
{"title":"Exercise promotes the functional integration of human stem cell-derived neural grafts in a rodent model of Parkinson's disease.","authors":"Niamh Moriarty, Tyra D Fraser, Cameron P J Hunt, Georgia Eleftheriou, Jessica A Kauhausen, Lachlan H Thompson, Clare L Parish","doi":"10.1016/j.stemcr.2025.102480","DOIUrl":"10.1016/j.stemcr.2025.102480","url":null,"abstract":"<p><p>Human pluripotent stem cell (hPSC)-derived dopamine neurons can functionally integrate and reverse motor symptoms in Parkinson's disease models, motivating current clinical trials. However, dopamine neuron proportions remain low and their plasticity inferior to fetal tissue grafts. Evidence shows exercise can enhance neuron survival and plasticity, warranting investigation for hPSC-derived neural grafts. We show voluntary exercise (wheel running) significantly increases graft plasticity, accelerating motor recovery in animals receiving ectopic, but not homotopic, placed grafts, suggestive of threshold requirements. Plasticity was accompanied by increased phosphorylated extracellular signal-regulated kinase (ERK+) cells in the graft (and host), reflective of mitogen-activated protein kinase (MAPK)-ERK signaling, a downstream target of glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), proteins that were also elevated. Verifying improved graft integration was the increase in cFos+ postsynaptic striatal neurons. These findings have direct implications for the adoption of physical therapy-based approaches to enhance neural transplantation outcomes in future Parkinson's disease clinical trials.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102480"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-24DOI: 10.1016/j.stemcr.2025.102482
Pierre Osteil, Sarah Withey, Nicole Santucci, Nader Aryamanesh, Ignatius Pang, Nazmus Salehin, Jane Sun, Annie Qin, Jiayi Su, Hilary Knowles, Xiucheng Bella Li, Simon Cai, Ernst Wolvetang, Patrick P L Tam
{"title":"MIXL1 activation in endoderm differentiation of human induced pluripotent stem cells.","authors":"Pierre Osteil, Sarah Withey, Nicole Santucci, Nader Aryamanesh, Ignatius Pang, Nazmus Salehin, Jane Sun, Annie Qin, Jiayi Su, Hilary Knowles, Xiucheng Bella Li, Simon Cai, Ernst Wolvetang, Patrick P L Tam","doi":"10.1016/j.stemcr.2025.102482","DOIUrl":"10.1016/j.stemcr.2025.102482","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (hiPSCs) possess the ability to differentiate into a multitude of cell and tissue types but display heterogeneous propensity of differentiation into specific lineage. Characterization of the transcriptome of 11 hiPSC lines showed that activation of MIXL1 at the early stage of stem cell differentiation correlated with higher efficacy in generating definitive endoderm and advancing differentiation and maturation of endoderm derivatives. Enforced expression of MIXL1 in the endoderm-inefficient hiPSCs enhanced the propensity of endoderm differentiation, suggesting that modulation of key drivers of lineage differentiation can re-wire hiPSC to the desired lineage propensity to generate the requisite stem cell products.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102482"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-17DOI: 10.1016/j.stemcr.2025.102477
Hafez Ismaili M'hamdi
{"title":"Language and labels from the lab: Definitions in the stem cell-based embryo model debate.","authors":"Hafez Ismaili M'hamdi","doi":"10.1016/j.stemcr.2025.102477","DOIUrl":"10.1016/j.stemcr.2025.102477","url":null,"abstract":"<p><p>This article examines the definitional challenges surrounding stem cell-based embryo models. Terms like \"synthetic embryos\" misrepresent their nature and influence public discourse. I argue for a multidisciplinary approach, integrating scientific precision with linguistic and ethical considerations, to ensure clarity, honesty, and respect in both scientific and societal debates.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102477"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.","authors":"Jinyuan Lu, Lixin Lv, Xiaoxue Tian, Zheng Li, Yuting Ma, Nannan Li, Jian Wang, Guangming Wang, Yu Zeng, Wenjun Zhang, Jun Xu, Aibin Liang","doi":"10.1016/j.stemcr.2025.102476","DOIUrl":"10.1016/j.stemcr.2025.102476","url":null,"abstract":"<p><p>Leukemic stem cells (LSCs) are a small subset of leukemia cells that drive leukemia initiation and maintenance. Herein, we report that CD37, a member of transmembrane 4 superfamily (TM4SF), regulates the survival of acute myeloid leukemia (AML) cells as well as the self-renewal of AML LSCs. The downregulation of CD37 retarded proliferation and increased apoptosis in human AML cell lines THP-1 and OCI-AML2. Deficiency of CD37 in vivo had a minimal effect on normal hematopoiesis but significantly impeded leukemia maintenance and propagation, which led to increased apoptosis and decreased cell cycle entry in AML blasts as well as impaired colony formation and declined frequency of AML LSCs in the serial transplantation. Furthermore, CD37 interacted with integrin α4β7 and activated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediated by integrin signaling. Our study provides novel insights for targeted therapy of AML, indicating CD37 as a safe and effective target for immunotherapy.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102476"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Perinuclear mitochondrial clustering for mesenchymal-to-epithelial transition in pluripotency induction.","authors":"Ge Xiang, Zihuang Liu, Zebin Yuan, Zhongfu Ying, Yingzhe Ding, Dongtong Lin, Haihao Qin, Shanshan Dong, Shihe Zhou, Hao Yuan, Wei Xie, Zhihong Zheng, Yongqiang Chen, Linpeng Li, Qi Long, Liang Yang, Yi Wu, Keshi Chen, Feixiang Bao, Yile Huang, Wei Li, Junwei Wang, Yang Liu, Dajiang Qin, Xingguo Liu","doi":"10.1016/j.stemcr.2025.102474","DOIUrl":"10.1016/j.stemcr.2025.102474","url":null,"abstract":"<p><p>Remodeled mitochondria are characteristic of pluripotent stem cells. However, a role for mitochondrial movement and distribution in pluripotency remains unknown. Here, we show that mitochondrial retrograde transport-mediated perinuclear clustering via dynein complex occurs at the early phase of pluripotency induction. Interestingly, this mitochondrial redistribution is regulated by Yamanaka factor OCT4 but not SOX2 or KLF4. This mitochondrial redistribution, which has effect on the efficiency of somatic cell reprogramming, also depends on DRP1-mediated mitochondrial fission. Importantly, perinuclear mitochondrial clustering is required for mesenchymal-to-epithelial transition (MET), an early step in reprogramming, during which β-catenin regulates the MET process. Furthermore, sufficient amount of β-catenin plays a key role in maintaining stabilization of E-CADHERIN. Taken together, these studies show that perinuclear mitochondrial clustering is an essential organellar step for MET process of pluripotency induction, which may shed light on the subcellular relationship between mitochondrial dynamics, pluripotency, and cellular morphology.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102474"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-03DOI: 10.1016/j.stemcr.2025.102472
Ana Cláudia Raposo, Paulo Caldas, Joana Jeremias, Maria Arez, Francisca Cazaux Mateus, Pedro Barbosa, Rui Sousa-Luís, Frederico Água, David Oxley, Annalisa Mupo, Melanie Eckersley-Maslin, Miguel Casanova, Ana Rita Grosso, Simão Teixeira da Rocha
{"title":"Gene reactivation upon erosion of X chromosome inactivation in female hiPSCs is predictable yet variable and persists through differentiation.","authors":"Ana Cláudia Raposo, Paulo Caldas, Joana Jeremias, Maria Arez, Francisca Cazaux Mateus, Pedro Barbosa, Rui Sousa-Luís, Frederico Água, David Oxley, Annalisa Mupo, Melanie Eckersley-Maslin, Miguel Casanova, Ana Rita Grosso, Simão Teixeira da Rocha","doi":"10.1016/j.stemcr.2025.102472","DOIUrl":"10.1016/j.stemcr.2025.102472","url":null,"abstract":"<p><p>Female human induced pluripotent stem cells frequently undergo X-chromosome inactivation (XCI) erosion, marked by X-inactive specific transcript (XIST) RNA loss and partial reactivation of the inactive X (Xi). This overlooked phenomenon limits our understanding of its impact on stem cell applications. Here, we show that XCI erosion is frequent and heterogeneous, leading to the reactivation of several X-linked genes. These are primarily located on the short arm of the X chromosome, particularly near escape genes and within H3K27me3-enriched domains, with reactivation linked to reduced promoter DNA methylation. Interestingly, escape genes further increase their expression from Xi upon XCI erosion, highlighting the critical role of XIST in their dosage regulation. Importantly, global (hydroxy)methylation levels and imprinted regions remain unaffected, and analysis of trilineage commitment and cardiomyocyte formation reveals that XCI erosion persists across differentiation. These findings underscore the need for greater awareness of the implications of XCI erosion for stem cell research and clinical applications.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102472"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-05-13Epub Date: 2025-04-17DOI: 10.1016/j.stemcr.2025.102475
Alejandro De Los Angeles
{"title":"Safeguarding genomic imprints in naive human pluripotency.","authors":"Alejandro De Los Angeles","doi":"10.1016/j.stemcr.2025.102475","DOIUrl":"10.1016/j.stemcr.2025.102475","url":null,"abstract":"<p><p>Naive human pluripotent stem cells (hPSCs) closely mirror the pre-implantation epiblast but risk imprint erosion under strong MEK/ERK inhibition, jeopardizing disease modeling and regenerative applications. In Stem Cell Reports, Fischer et al. show that partial MEK/ERK inhibition plus ZFP57 overexpression crucially preserves parent-of-origin DNA methylation, thereby offering more faithful and stable naive hPSC models.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102475"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}