Stem Cell ReportsPub Date : 2025-03-28DOI: 10.1016/j.stemcr.2025.102478
Jacob A Klickstein, Michelle A Johnson, Pantelis Antonoudiou, Jamie Maguire, Joao A Paulo, Steve P Gygi, Chris Weihl, Malavika Raman
{"title":"ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.","authors":"Jacob A Klickstein, Michelle A Johnson, Pantelis Antonoudiou, Jamie Maguire, Joao A Paulo, Steve P Gygi, Chris Weihl, Malavika Raman","doi":"10.1016/j.stemcr.2025.102478","DOIUrl":"https://doi.org/10.1016/j.stemcr.2025.102478","url":null,"abstract":"","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102478"},"PeriodicalIF":5.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-25DOI: 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":"https://doi.org/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":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-25DOI: 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":"https://doi.org/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":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-24DOI: 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":"https://doi.org/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":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-18DOI: 10.1016/j.stemcr.2025.102470
Christopher A Procyk, Anna Melati, Joana Ribeiro, Jingshu Liu, Matthew J Branch, Jamie D Delicata, Menahil Tariq, Aikaterini A Kalarygrou, Jessica Kapadia, Majid Moshtagh Khorsani, Emma L West, Alexander J Smith, Anai Gonzalez-Cordero, Robin R Ali, Rachael A Pearson
{"title":"Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis.","authors":"Christopher A Procyk, Anna Melati, Joana Ribeiro, Jingshu Liu, Matthew J Branch, Jamie D Delicata, Menahil Tariq, Aikaterini A Kalarygrou, Jessica Kapadia, Majid Moshtagh Khorsani, Emma L West, Alexander J Smith, Anai Gonzalez-Cordero, Robin R Ali, Rachael A Pearson","doi":"10.1016/j.stemcr.2025.102470","DOIUrl":"https://doi.org/10.1016/j.stemcr.2025.102470","url":null,"abstract":"<p><p>Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1<sup>-/-</sup> model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102470"},"PeriodicalIF":5.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-12DOI: 10.1016/j.stemcr.2025.102447
Tomas Zikmund, Jonathan Fiorentino, Chris Penfold, Marco Stock, Polina Shpudeiko, Gaurav Agarwal, Larissa Langfeld, Kseniya Petrova, Leonid Peshkin, Stephan Hamperl, Antonio Scialdone, Eva Hoermanseder
{"title":"Differentiation success of reprogrammed cells is heterogeneous in vivo and modulated by somatic cell identity memory.","authors":"Tomas Zikmund, Jonathan Fiorentino, Chris Penfold, Marco Stock, Polina Shpudeiko, Gaurav Agarwal, Larissa Langfeld, Kseniya Petrova, Leonid Peshkin, Stephan Hamperl, Antonio Scialdone, Eva Hoermanseder","doi":"10.1016/j.stemcr.2025.102447","DOIUrl":"10.1016/j.stemcr.2025.102447","url":null,"abstract":"<p><p>Nuclear reprogramming can change cellular fates. Yet, reprogramming efficiency is low, and the resulting cell types are often not functional. Here, we used nuclear transfer to eggs to follow single cells during reprogramming in vivo. We show that the differentiation success of reprogrammed cells varies across cell types and depends on the expression of genes specific to the previous cellular identity. We find subsets of reprogramming-resistant cells that fail to form functional cell types, undergo cell death, or disrupt normal body patterning. Reducing expression levels of genes specific to the cell type of origin leads to better reprogramming and improved differentiation trajectories. Thus, our work demonstrates that failing to reprogram in vivo is cell type specific and emphasizes the necessity of minimizing aberrant transcripts of the previous somatic identity for improving reprogramming.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102447"},"PeriodicalIF":5.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-12DOI: 10.1016/j.stemcr.2025.102452
Stefania Apostolou, Vanessa Donega
{"title":"Embracing the heterogeneity of neural stem cells in the subventricular zone.","authors":"Stefania Apostolou, Vanessa Donega","doi":"10.1016/j.stemcr.2025.102452","DOIUrl":"https://doi.org/10.1016/j.stemcr.2025.102452","url":null,"abstract":"<p><p>Neural stem cells (NSCs) of the subventricular zone (SVZ) could be a potential source for brain repair. These are heterogeneous cells with distinct activation states. To identify NSCs in the SVZ, different markers are used, including Gfap, Nestin, and Sox2. A comparison of these different methods to assess if the NSC marker used is selective toward specific NSC states is currently lacking. Here, we integrated six previously published single-cell RNA sequencing datasets from the adult mouse SVZ, where different methods were used to identify NSCs. Our data show that the approach used to isolate NSCs favors certain cell states over others. Our analyses underscore the importance of enriching for the NSC population of interest to increase data granularity. We also observed that cells with lower gene expression can be assigned incorrectly to clusters. We provide a framework for choosing the most optimal approach to enrich for NSC states of interest.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102452"},"PeriodicalIF":5.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2025-03-11Epub Date: 2025-02-27DOI: 10.1016/j.stemcr.2025.102424
Ying Xue Lv, Qi You Li, Ping Duan, Min Fang Zhang, Bo Liu, Shi Ying Li, Tong Tao Zhao, Hao Wang, Yong Liu, Zheng Qin Yin
{"title":"Safe CNV removal is crucial for successful hESC-RPE transplantation in wet age-related macular degeneration.","authors":"Ying Xue Lv, Qi You Li, Ping Duan, Min Fang Zhang, Bo Liu, Shi Ying Li, Tong Tao Zhao, Hao Wang, Yong Liu, Zheng Qin Yin","doi":"10.1016/j.stemcr.2025.102424","DOIUrl":"10.1016/j.stemcr.2025.102424","url":null,"abstract":"<p><p>Subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells has demonstrated therapeutic potential in macular degeneration. However, its efficiency is limited in wet age-related macular degeneration (wet AMD) due to choroidal neovascularization (CNV). To investigate the feasibility of hESC-RPE cell transplantation, we employed a surgical approach to induce retinal detachment, which allowed the removal of CNV lesions. After retinal reattachment, hESC-RPE cells were transplanted into the subretinal space. Ten patients were enrolled and divided into 2 groups. No retinal edema or CNV recurrence was observed in group 1 (7 patients without bleeding). Group 2 (3 patients with bleeding) had persistent fundus inflammation, and one patient experienced CNV recurrence. All patients were managed effectively without vision loss. These findings suggest that subretinal transplantation of hESC-RPE cells after CNV removal is safe and well tolerated; however, damage caused during CNV removal may trigger persistent inflammation and CNV recurrence. This study was registered at ClinicalTrials.gov (NCT02749734).</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102424"},"PeriodicalIF":5.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531796","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 : 2025-03-11DOI: 10.1016/j.stemcr.2025.102467
Saif F Dababneh, Hosna Babini, Verónica Jiménez-Sábado, Sheila S Teves, Kyoung-Han Kim, Glen F Tibbits
{"title":"Dissecting cardiovascular disease-associated noncoding genetic variants using human iPSC models.","authors":"Saif F Dababneh, Hosna Babini, Verónica Jiménez-Sábado, Sheila S Teves, Kyoung-Han Kim, Glen F Tibbits","doi":"10.1016/j.stemcr.2025.102467","DOIUrl":"https://doi.org/10.1016/j.stemcr.2025.102467","url":null,"abstract":"<p><p>Advancements in genomics have revealed hundreds of loci associated with cardiovascular diseases, highlighting the role genetic variants play in disease pathogenesis. Notably, most variants lie within noncoding genomic regions that modulate transcription factor binding, chromatin accessibility, and thereby the expression levels and cell type specificity of gene transcripts. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a powerful tool to delineate the pathogenicity of such variants and elucidate the underlying transcriptional mechanisms. Our review discusses the basics of noncoding variant-mediated pathogenesis, the methodologies utilized, and how hiPSC-based heart models can be leveraged to dissect the mechanisms of noncoding variants.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102467"},"PeriodicalIF":5.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}