Stem Cell ReportsPub Date : 2025-06-10Epub Date: 2025-05-22DOI: 10.1016/j.stemcr.2025.102509
Liang Li, Brian J Feldman
{"title":"Characterization and lineage tracing of a mouse adipose depot reveal properties conserved with human supraclavicular brown adipose tissue.","authors":"Liang Li, Brian J Feldman","doi":"10.1016/j.stemcr.2025.102509","DOIUrl":"10.1016/j.stemcr.2025.102509","url":null,"abstract":"<p><p>Enhancing energy utilization by increasing the number or activity of beige adipocytes has the potential to be of therapeutic benefit for a broad range of metabolic disorders. However, knowledge gaps in our understanding of the mouse versus human developmental origins of beige fat have inhibited the generation of robust preclinical models, leaving a barrier to the success of therapies. Here, we report that a distinct inguinal beige adipose tissue (ibAT) depot lineage traces to the same Prx1+ cell origins as inguinal white adipose tissue (iWAT) but maintains higher thermogenic activity and capability during aging. We discovered that ibAT has the morphological appearance of human supraclavicular brown adipose tissue (scBAT) and, importantly, conserved molecular markers and developmental origins with human scBAT. Our findings reveal a distinct mouse beige adipose tissue depot and provide a preclinical model of human beige adipose tissue development and maintenance.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102509"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132021","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 : 2025-06-10DOI: 10.1016/j.stemcr.2025.102514
Amander T Clark, Heidi Cook-Andersen, Sarah Franklin, Rosario Isasi, Debra J H Mathews, Vincent Pasque, Peter J Rugg-Gunn, Patrick P L Tam, Hongmei Wang, Jan J Zylicz, Janet Rossant
{"title":"Stem cell-based embryo models: The 2021 ISSCR stem cell guidelines revisited.","authors":"Amander T Clark, Heidi Cook-Andersen, Sarah Franklin, Rosario Isasi, Debra J H Mathews, Vincent Pasque, Peter J Rugg-Gunn, Patrick P L Tam, Hongmei Wang, Jan J Zylicz, Janet Rossant","doi":"10.1016/j.stemcr.2025.102514","DOIUrl":"10.1016/j.stemcr.2025.102514","url":null,"abstract":"<p><p>Human stem cell-based embryo models (SCBEMs) are a research technology with the potential to facilitate our understanding of human embryogenesis, improve assisted reproductive technology outcomes, elucidate the causes of early pregnancy failure, and provide a clearer understanding of the developmental origins of disease. Given that human SCBEMs are designed to model specific phenotypic features and developmental processes of human embryos, they raise distinct concerns from other stem cell models, such as organoids. The International Society for Stem Cell Research (ISSCR) Guidelines for Stem Cell Research and Clinical Translation, published in 2021, made recommendations for research oversight of SCBEMs and established different categories of review based on involvement of embryonic and extraembryonic lineages. However, recent progress has enabled unexpected ways to create increasingly complex models, as well as more efficient means of doing so without including all major extraembryonic lineages. A working group was tasked by the ISSCR executive to undertake a thorough reexamination of the guidelines in the light of these advances. The three main recommendations of the working group are that all research involving organized 3-dimensional human SCBEMs (1) should be subject to appropriate review, (2) must have a clear scientific rationale, and (3) must be subject to limited timelines. The proposed modifications to the ISSCR guidelines are intended to bring more clarity to the field, help guide the deliberations of researchers, oversight committees and other relevant stakeholders, and ensure continued public confidence.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":"20 6","pages":"102514"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275910","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 : 2025-06-10Epub Date: 2025-05-08DOI: 10.1016/j.stemcr.2025.102504
Swikriti Shrestha, Lauren T Jennings, Kyle Knofczynski, Sharath B Shivakumar, Quinn P Peterson
{"title":"Modeling diabetic alpha cell dysfunction using stem cell-derived alpha cells.","authors":"Swikriti Shrestha, Lauren T Jennings, Kyle Knofczynski, Sharath B Shivakumar, Quinn P Peterson","doi":"10.1016/j.stemcr.2025.102504","DOIUrl":"10.1016/j.stemcr.2025.102504","url":null,"abstract":"<p><p>Dysfunction of pancreatic alpha cells contributes to the pathophysiology of diabetes. Features of diabetic alpha cell dysfunction include glucagon hypersecretion, defects in proglucagon processing, and altered transcriptomic profile. The lack of an in vitro human alpha cell model has prevented the investigation, and potential correction, of these dysfunctional phenotypes. Here, we show that induction of endoplasmic reticulum (ER) stress in stem cell-derived alpha (SC-α) cells induces hypersecretion of glucagon. ER stress also increases the secretion of glicentin and the expression of glucagon-like peptide-1 (GLP-1), peptides produced by alternate cleavage of proglucagon by the prohormone convertase 1 (PC1/3) enzyme. Additionally, ER stress establishes a diabetic transcriptional state in SC-α cells characterized by downregulation of MAFB, as well as glycolysis and oxidative phosphorylation pathways. We show that sunitinib, a tyrosine kinase inhibitor, protects SC-α cells against the ER stress-induced glucagon hypersecretion phenotype. Thus, SC-α cell model can advance our knowledge of islets in health and diabetes.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102504"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017629","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 : 2025-06-10Epub Date: 2025-05-15DOI: 10.1016/j.stemcr.2025.102505
Dusko Ilic
{"title":"Engineered proxies and the illusion of de-extinction.","authors":"Dusko Ilic","doi":"10.1016/j.stemcr.2025.102505","DOIUrl":"10.1016/j.stemcr.2025.102505","url":null,"abstract":"<p><p>The recent creation of dire wolf-like canids by Colossal Biosciences marks a technical achievement in genome editing and synthetic embryology. But the project also demands a reevaluation of what we mean by \"de-extinction\"-and whether a phenotypic approximation constitutes species restoration.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102505"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086732","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 : 2025-06-10Epub Date: 2025-05-22DOI: 10.1016/j.stemcr.2025.102507
Rebecca Z Weber, Ruslan Rust, Christian Tackenberg
{"title":"How neural stem cell therapy promotes brain repair after stroke.","authors":"Rebecca Z Weber, Ruslan Rust, Christian Tackenberg","doi":"10.1016/j.stemcr.2025.102507","DOIUrl":"10.1016/j.stemcr.2025.102507","url":null,"abstract":"<p><p>The human brain has a very limited capacity for self-repair, presenting significant challenges in recovery following injuries such as ischemic stroke. Stem cell-based therapies have emerged as promising strategies to enhance post-stroke recovery. Building on a large body of preclinical evidence, clinical trials are currently ongoing to prove the efficacy of stem cell therapy in stroke patients. However, the mechanisms through which stem cell grafts promote neural repair remain incompletely understood. Key questions include whether these effects are primarily driven by (1) the secretion of trophic factors that stimulate endogenous repair processes, (2) direct neural cell replacement, or (3) a combination of both mechanisms. This review explores the latest advancements in neural stem cell therapy for stroke, highlighting research insights in brain repair mechanisms. Deciphering the fundamental mechanisms underlying stem cell-mediated brain regeneration holds the potential to refine therapeutic strategies and advance treatments for a range of neurological disorders.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102507"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132080","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 : 2025-06-10Epub Date: 2025-05-29DOI: 10.1016/j.stemcr.2025.102511
Jielin Yan, Renhe Luo, Bess P Rosen, Dingyu Liu, Wilfred Wong, Christina S Leslie, Danwei Huangfu
{"title":"Discovery of NANOG enhancers and their essential roles in self-renewal and differentiation in human embryonic stem cells.","authors":"Jielin Yan, Renhe Luo, Bess P Rosen, Dingyu Liu, Wilfred Wong, Christina S Leslie, Danwei Huangfu","doi":"10.1016/j.stemcr.2025.102511","DOIUrl":"10.1016/j.stemcr.2025.102511","url":null,"abstract":"<p><p>Human embryonic stem cells (hESCs) are notable for their ability to self-renew and to differentiate into all tissue types in the body. NANOG is a core regulator of hESC identity, and dynamic control of its expression is crucial to maintain the balance between self-renewal and differentiation. Transcriptional regulation depends on enhancers, but NANOG enhancers in hESCs are not well characterized. Here, we report two NANOG enhancers discovered from a CRISPR interference screen in hESCs. Deletion of a single copy of either enhancer significantly reduced NANOG expression, compromising self-renewal and increasing differentiation propensity. Interestingly, these two NANOG enhancers are involved in a tandem duplication event found in certain primates including humans but not in mice. However, the duplicated counterparts do not regulate NANOG expression. This work expands our knowledge of functional enhancers in hESCs and highlights the sensitivity of the hESC state to the dosage of core regulators and their enhancers.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102511"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188047","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 : 2025-06-10DOI: 10.1016/j.stemcr.2025.102532
James E Mason, Xiaokai Nie, Daniel Coca, Peter W Andrews
{"title":"Stem cell fate decisions: Substates and attractors.","authors":"James E Mason, Xiaokai Nie, Daniel Coca, Peter W Andrews","doi":"10.1016/j.stemcr.2025.102532","DOIUrl":"10.1016/j.stemcr.2025.102532","url":null,"abstract":"<p><p>Heterogeneity of gene expression is a characteristic of stem cell populations. Here, we review our own findings with human pluripotent stem cells, emphasizing their capacity to occupy distinct metastable substates that influence their differentiation outcomes. Experimental studies, such as single-cell transcriptomics and analyses of marker dynamics, demonstrate the transient and dynamic nature of these substates. Based on a novel approach to model sequences of fluorescent marker distributions over time, we suggest that transitions between these substates may be governed by deterministic chaos in addition to stochastic fluctuations of gene expression, both of which likely contribute to the observed dynamic behavior.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":"20 6","pages":"102532"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275909","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":"Leveraging CRISPR activation for rapid assessment of gene editing products in human pluripotent stem cells.","authors":"Youjun Wu, Aaron Zhong, Alessandro Evangelisti, Mega Sidharta, Huangfu Danwei, Lorenz Studer, Ting Zhou","doi":"10.1016/j.stemcr.2025.102499","DOIUrl":"10.1016/j.stemcr.2025.102499","url":null,"abstract":"<p><p>Verification of genome editing in human pluripotent stem cells (hPSCs), particularly at silent loci, is desirable but challenging, as it often requires complex and time-intensive differentiation to induce their expression. Here, we establish a rapid and effective workflow for verifying genome-edited hPSC lines targeting unexpressed genes using CRISPR-mediated transcriptional activation (CRISPRa). We systematically compared the efficiency of various CRISPRa systems and identified the synergistic activation mediator (SAM) system as the most potent for activating silent genes in hPSCs. Furthermore, combining SAM with TET1, a demethylation module, enhanced the activation of methylated genes. By inducing targeted gene activation in undifferentiated hPSCs using CRISPRa, we successfully verified single- and dual-reporter lines, functionally tested degradation tag (dTAG) knockins, and validated silent gene knockouts within 48 h. This approach bypasses the need to induce target gene expression through differentiation, providing a rapid and effective assay for verifying silent gene editing at the hPSC stage.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102499"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038265","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 : 2025-06-10Epub Date: 2025-05-22DOI: 10.1016/j.stemcr.2025.102506
Amanda Ya, Chenhui Deng, Kristina M Godek
{"title":"Cell competition eliminates aneuploid human pluripotent stem cells.","authors":"Amanda Ya, Chenhui Deng, Kristina M Godek","doi":"10.1016/j.stemcr.2025.102506","DOIUrl":"10.1016/j.stemcr.2025.102506","url":null,"abstract":"<p><p>Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite frequent mitotic errors that cause aneuploidy or chromosome imbalances. Consequently, aneuploid hPSC propagation must be prevented to sustain genome stability, but how this is achieved is unknown. Surprisingly, we find that, unlike somatic cells, uniformly aneuploid hPSC populations with heterogeneous abnormal karyotypes proliferate. Instead, in mosaic populations, cell-non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells, regardless of specific chromosome imbalances. Aneuploid hPSCs with lower MYC or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain an advantage when MYC and p53 relative abundance switches. Thus, MYC- and p53-driven cell competition preserves hPSC genome integrity despite their low mitotic fidelity and intrinsic capacity to proliferate with an aneuploid genome. These findings have important implications for using hPSCs in regenerative medicine and for how diploid human embryos form during development despite the prevalence of aneuploidy.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102506"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133292","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 : 2025-06-10Epub Date: 2025-05-29DOI: 10.1016/j.stemcr.2025.102510
Luqman Ellythy, Mohamed Addani, Zubin Master
{"title":"An analysis of stem cell training programs for physicians in the US-A mirage of credibility.","authors":"Luqman Ellythy, Mohamed Addani, Zubin Master","doi":"10.1016/j.stemcr.2025.102510","DOIUrl":"10.1016/j.stemcr.2025.102510","url":null,"abstract":"<p><p>Analyzing stem cell training businesses for United States (US) physicians shows the use of sensationalized marketing language emphasizing profits and growth with many of the instructors affiliated with clinics providing unproven therapies. We argue that many current pedagogical offerings for physicians interested in stem cell interventions are likely to offer questionable training and outline red flags for physicians interested in stem cell therapies.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102510"},"PeriodicalIF":5.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188046","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}