Stem Cell ReportsPub Date : 2026-07-14Epub Date: 2026-06-25DOI: 10.1016/j.stemcr.2026.102972
Ahmed S Shams, Lalitha S Denduluri, Megan K Sumera, Ingrid R Aragon, Lauren LaScala, Jae Hwi Sung, Sydney Peng, Sarah J Cornelius, Sana Ikramuddin, Aiden M Boechler, Eric Batchelor, Michael Kyba, Julia C Liu
{"title":"Elevated mitochondrial Ca<sup>2+</sup> impairs satellite cell pool expansion in response to skeletal muscle injury.","authors":"Ahmed S Shams, Lalitha S Denduluri, Megan K Sumera, Ingrid R Aragon, Lauren LaScala, Jae Hwi Sung, Sydney Peng, Sarah J Cornelius, Sana Ikramuddin, Aiden M Boechler, Eric Batchelor, Michael Kyba, Julia C Liu","doi":"10.1016/j.stemcr.2026.102972","DOIUrl":"10.1016/j.stemcr.2026.102972","url":null,"abstract":"<p><p>MICU1 loss-of-function variants in human patients are associated with proximal muscle weakness and myopathy. Mitochondrial Ca<sup>2+</sup> levels are basally elevated when MICU1, the gatekeeper of the mitochondrial Ca<sup>2+</sup> uniporter, is absent. The importance of regulating mitochondrial Ca<sup>2+</sup> in skeletal muscle has generally been studied in mature muscle fibers. How satellite cells are impacted by mitochondrial Ca<sup>2+</sup> dysregulation is poorly understood. We investigated Micu1 deletion specifically in Pax7+ satellite cells to address this gap in knowledge. Colony-forming activity in vitro was unaffected in Micu1-deficient satellite cells, but colony sizes were smaller. Although satellite cell homeostasis was not significantly affected 1 month following Micu1 deletion, the regenerative response post-injury was significantly impaired. Satellite cell self-renewal from Micu1-deficient donor cells in transplant recipients was also heavily compromised. Our data suggest that properly gating mitochondrial Ca<sup>2+</sup> import via the uniporter is integral to satellite cell activation from quiescence in response to muscle injury.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102972"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333357","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":"Suppression of ATM kinase signaling accelerates cellular senescence.","authors":"Kei-Ichi Ishikawa, Takahiro Shiga, Takumi Hirose, Naoko Kuzumaki, Sakura Miyoshi, Akihiro Yamaguchi, Hidetaka Tamune, Avijite Kumer Sarkar, Kento Nakai, Kazuyoshi Baba, Shigeo Okabe, Nobutaka Hattori, Hideyuki Okano, Wado Akamatsu","doi":"10.1016/j.stemcr.2026.102956","DOIUrl":"10.1016/j.stemcr.2026.102956","url":null,"abstract":"<p><p>Cells derived from rejuvenated human induced pluripotent stem cells (hiPSCs) require extended culture periods to achieve functional maturation, and it remains difficult to recapitulate cellular senescence in these cells in vitro. This limitation hinders the accurate and efficient modeling of age-related neurodegenerative diseases. Here, we aimed to establish a simple approach to promote neuronal maturation and improve the efficiency of hiPSC-based disease modeling. Using a small-molecule inhibitor library, we identified an ATM kinase inhibitor, KU60019, that promotes both maturation-associated features and senescence-associated phenotypes in hiPSC-derived neurons and fibroblasts. KU60019 treatment promoted the manifestation of disease-relevant phenotypes in hiPSC models of age-related neurodegenerative diseases. Furthermore, senolytic analyses suggested that KU60019-induced senescent cells depend on pro-survival pathways, including HSP90-associated signaling. These findings suggest that KU60019 provides a simple and useful tool for accelerating phenotypic recapitulation in hiPSC models of age-related neurodegenerative diseases.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102956"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148228565","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":"Adipose precursor cell-derived clusterin promotes homeostasis in subcutaneous adipose tissue.","authors":"Zong Chen, Zhiyou Chen, Jiuzuo Huang, Nanze Yu, Xinyan Chen, Yuming Chong, Hao Liu, Xiaolei Jin, Xueying Hou, Xiao Long","doi":"10.1016/j.stemcr.2026.102969","DOIUrl":"10.1016/j.stemcr.2026.102969","url":null,"abstract":"<p><p>Adipose precursor cells (APCs), present within the stromal vascular fraction (SVF) of adipose tissue, play an important role in adipose biology. However, its regulatory functions in adipogenesis and tissue homeostasis remain incompletely characterized. Here, we isolated APC from the subcutaneous adipose tissue of Prx1-Cre; Rosa26-tdTomato mice and confirmed that APC has a high adipogenic differentiation efficiency. Next, RNA sequencing analysis indicates that APC may have dual effects of promoting adipogenesis and anti-inflammatory effects. Subsequent in vivo studies identified clusterin (Clu) as a key secretory factor through which APC exerts its regulatory functions. By utilizing gene regulation and APC/adipocyte co-culture, we further demonstrated that APC-derived Clu promotes its own adipogenic differentiation and improves local resistance to oxidative stress. Collectively, data from conditional Clu knockout mice establish its key function in preserving adipose tissue homeostasis. These findings highlight Clu as a potential therapeutic target for interventions aimed at adipose tissue homeostasis and regeneration.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102969"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278783","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 : 2026-07-14Epub Date: 2026-06-25DOI: 10.1016/j.stemcr.2026.102971
Galbha Duggal, Xinyu Li, Philippa Pettingill, Tatjana Lalic, Shailesh Kumar Gupta, Christine Flodgaard Høgsbro, Viola Volpato, Caleb Webber, Rory Bowden, Despoina Charou, Kanisa Arunasalam, Marcello Maresca, Ryan Hicks, Satyan Chintawar, M Zameel Cader
{"title":"A highly efficient method to differentiate CGRP-expressing peptidergic nociceptors from human induced pluripotent stem cells.","authors":"Galbha Duggal, Xinyu Li, Philippa Pettingill, Tatjana Lalic, Shailesh Kumar Gupta, Christine Flodgaard Høgsbro, Viola Volpato, Caleb Webber, Rory Bowden, Despoina Charou, Kanisa Arunasalam, Marcello Maresca, Ryan Hicks, Satyan Chintawar, M Zameel Cader","doi":"10.1016/j.stemcr.2026.102971","DOIUrl":"10.1016/j.stemcr.2026.102971","url":null,"abstract":"<p><p>Pain disorders such as neuropathic pain and headache remain areas of considerable unmet need and considered high risk by pharma. Human-induced pluripotent stem cells (iPSC)-derived sensory neurons have already been used to accelerate translational research but the current differentiation protocols produce non-peptidergic nociceptors. We demonstrate for the first time the robust differentiation of hiPSC into peptidergic nociceptor lineage with high yield. These nociceptors express CGRP and TRPV1 and show functional maturity including the expression of TTX-resistant currents and responding to TRPV1 and TRPA1 agonists. Importantly, they were able to release CGRP basally and upon stimulation by inflammatory soup, which was inhibited upon the application of the 5-HT<sub>1B/1D/1F</sub> agonist, sumatriptan, a migraine prophylactic drug. We report the successful generation of a novel in vitro functional peptidergic nociceptor model which will allow investigation of disease mechanisms in pain and translational phenotypic drug screening for new effective pain therapies.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102971"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333307","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 : 2026-07-14Epub Date: 2026-06-09DOI: 10.1016/j.stemcr.2026.102933
Alexander Stanton, Selcan Aydin, Daniel A Skelly, Tracy McGarr, Dylan Stavish, Kim Leonhard, Seth Taapken, Tenneille Ludwig, Erik McIntire, Matthew Pankratz, Anne Czechanski, Ted Choi, Steven P Gygi, Ivana Barbaric, Thomas Vierbuchen, Steven C Munger, Laura G Reinholdt, Martin F Pera
{"title":"Chromosome X dosage modulates development of aneuploidy in genetically diverse mouse embryonic stem cells.","authors":"Alexander Stanton, Selcan Aydin, Daniel A Skelly, Tracy McGarr, Dylan Stavish, Kim Leonhard, Seth Taapken, Tenneille Ludwig, Erik McIntire, Matthew Pankratz, Anne Czechanski, Ted Choi, Steven P Gygi, Ivana Barbaric, Thomas Vierbuchen, Steven C Munger, Laura G Reinholdt, Martin F Pera","doi":"10.1016/j.stemcr.2026.102933","DOIUrl":"10.1016/j.stemcr.2026.102933","url":null,"abstract":"<p><p>The genetic integrity of pluripotent stem cells (PSC) is critical to their applications in research and therapy, but it is compromised by frequent development of structural chromosome variants associated with malignancy. Many PSC lines exhibit remarkable genetic stability, but little is known about the basis of the known variation in genomic integrity among different PSC isolates. Here, we identify aneuploidies using RNA-seq and proteomics data from a panel of mouse embryonic stem cell (mESC) lines derived from 170 Diversity Outbred mice. We found 62 lines with detectable aneuploid subpopulations and a subset of originally XX lines that lost one chromosome X (XO). Strikingly, a much lower proportion of XX lines were aneuploid, compared to XY or XO lines. Two single-cell RNA-seq datasets demonstrated that aneuploid XY DO mESC also show lower chromosome X gene expression, and a prospective study confirmed that XY mESC accumulate higher aneuploid proportions in culture than isogenic XX lines. We identify potential mechanisms for this protective effect of X chromosome dosage, including our findings that the lines with two active X chromosomes have a higher proportion of 2-cell-like cells and higher expression of X-linked tumor suppressor genes, both features associated with the maintenance of genomic integrity, and that they compete more robustly in co-culture with chromosomally abnormal cells than XY cells.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102933"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212357","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 : 2026-07-14Epub Date: 2026-06-18DOI: 10.1016/j.stemcr.2026.102962
Samira Vera-Choqqueccota, Drew Ehrlich, Vladimir Luna-Gomez, Sebastian Hernandez, Jesus Gonzalez-Ferrer, Hunter E Schweiger, Kateryna Voitiuk, Yohei Rosen, Kivilcim Doganyigit, Isabel Cline, Rebecca Ward, Erika Yeh, Karen H Miga, Barbara Des Rochers, Sri Kurniawan, David Haussler, Kristian López Vargas, Mircea Teodorescu, Mohammed A Mostajo-Radji
{"title":"Cloud-connected pluripotent stem cell platform enhances scientific identity in underrepresented students.","authors":"Samira Vera-Choqqueccota, Drew Ehrlich, Vladimir Luna-Gomez, Sebastian Hernandez, Jesus Gonzalez-Ferrer, Hunter E Schweiger, Kateryna Voitiuk, Yohei Rosen, Kivilcim Doganyigit, Isabel Cline, Rebecca Ward, Erika Yeh, Karen H Miga, Barbara Des Rochers, Sri Kurniawan, David Haussler, Kristian López Vargas, Mircea Teodorescu, Mohammed A Mostajo-Radji","doi":"10.1016/j.stemcr.2026.102962","DOIUrl":"10.1016/j.stemcr.2026.102962","url":null,"abstract":"<p><p>Stem cell research offers unique opportunities for authentic scientific engagement, yet infrastructure requirements have confined participation to elite institutions, perpetuating workforce disparities. We developed an integrated framework combining stem cell engineering, cloud-connected microscopy, and psychometric assessment. The framework integrates a doxycycline-inducible NGN2 mouse embryonic stem cell (mESC) system, low-cost cloud microscopy, and the Stem Cell Research Identity Scale (SCRIS). Implementation across a high school and a community college demonstrated significant increases in scientific identity. Students using differentiating PSCs showed broader science identity gains than those using neuroblastoma cells, particularly in competence, research readiness, and recognition. High school students showed enhanced research competence gains compared to community college students despite equivalent intervention duration. Demographic analyses revealed enhanced effectiveness for Hispanic and first-generation college students. This framework provides a scalable model for broadening participation in biomedical research.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102962"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278737","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 : 2026-07-14Epub Date: 2026-06-18DOI: 10.1016/j.stemcr.2026.102964
Bao Q Thai, Elizabeth J Sargent, Stephanie A Luff, Colin A Fields, Jared M Churko, Jonathan N Young, Anthony Bosco, Christopher M Sturgeon, Deepta Bhattacharya
{"title":"WNT signaling in human pluripotent stem cells promotes HDAC2-dependent epigenetic programs and development of retinoic acid-responsive mesoderm.","authors":"Bao Q Thai, Elizabeth J Sargent, Stephanie A Luff, Colin A Fields, Jared M Churko, Jonathan N Young, Anthony Bosco, Christopher M Sturgeon, Deepta Bhattacharya","doi":"10.1016/j.stemcr.2026.102964","DOIUrl":"10.1016/j.stemcr.2026.102964","url":null,"abstract":"<p><p>Human pluripotent stem cells (hPSCs) can be used as a scalable source of lymphocytes for adoptive cell therapies, contingent on the robust generation of definitive hematopoietic intermediates. Early WNT activation with CHIR99021 during mesoderm induction promoted the formation of KDR+ ALDH1A2+ mesoderm, which is essential for subsequent generation of T cells in a retinoic acid (RA)-dependent manner. Integrated scRNA-seq and ATAC-seq defined a WNT-dependent developmental trajectory from hPSCs to KDR+ ALDH1A2+ mesoderm. Gene regulatory network modeling predicted HDAC2 and E-box transcription factors as regulators of RA-responsive mesodermal differentiation downstream of WNT. HDAC2 knockout impaired, while HDAC2 overexpression enhanced KDR+ ALDH1A2+ mesoderm formation. E-box factor manipulation had no discernible effect. An orthogonal chemical screen confirmed that HDAC2 inhibition suppressed KDR+ ALDH1A2+ mesoderm, whereas modulating histone methylation enhanced their formation. These findings reveal mechanisms by which WNT signaling promotes RA-responsive mesoderm, and they suggest methods to improve the generation of lymphocytes from hPSCs.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102964"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278866","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":"Targeting CCDC90B restores intestinal stem cell function under hyperuricemic stress.","authors":"Xiuying Peng, Moxuan Li, Kaixuan Zeng, Wantong Lv, Shuai Huang, Zhaopeng Chen, Yunwei Guo, Taoli Liu, Fengping Zheng, Peng Huang","doi":"10.1016/j.stemcr.2026.102970","DOIUrl":"10.1016/j.stemcr.2026.102970","url":null,"abstract":"<p><p>Hyperuricemia (HUA) affects diverse biological processes and signaling pathways across multiple organ systems; however, its impact on the intestine remains poorly understood. Here, we show that HUA disrupts intestinal barrier function primarily by impairing intestinal stem cell (ISC) function, which is essential for epithelial renewal. Mechanistically, elevated uric acid (UA) directly binds to the mitochondrial protein CCDC90B, leading to excessive mitochondrial ROS accumulation, activation of the NLRP3 inflammasome, and subsequent initiation of downstream pyroptotic signaling. The resulting exhaustion of the intestinal stem cell pool impairs epithelial regeneration and further weakens intestinal barrier integrity. Collectively, these findings reveal a previously unrecognized mechanism linking UA to ISC dysfunction and highlight CCDC90B as a potential therapeutic target for HUA-associated intestinal dysfunction.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102970"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278910","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 : 2026-07-14Epub Date: 2026-06-18DOI: 10.1016/j.stemcr.2026.102963
Songqin Yang, Zhikai Ye, Lu Lin, Zhenlong Jiang, Erkang Wang, Jin Wang
{"title":"KDM8 acts as a co-regulator of transcription factor SOX2 for promoting cell pluripotency.","authors":"Songqin Yang, Zhikai Ye, Lu Lin, Zhenlong Jiang, Erkang Wang, Jin Wang","doi":"10.1016/j.stemcr.2026.102963","DOIUrl":"10.1016/j.stemcr.2026.102963","url":null,"abstract":"<p><p>iPSCs have drawn significant attention for their biomedical potential, yet reprogramming remains inefficient and the underlying mechanisms are incompletely defined. KDM8, a histone demethylase, is known to play critical roles in processes such as cell-cycle regulation and embryonic development; nevertheless, its function in reprogramming has not been reported. Our investigations demonstrate that KDM8 significantly enhances the reprogramming efficiency mediated by the canonical Yamanaka factors. Remarkably, KDM8, in combination with OCT4 alone, is sufficient to reprogram somatic cells. Further analyses reveal that KDM8 facilitates reprogramming through a dual regulatory mechanism. On one hand, KDM8 leverages its canonical enzymatic activity to reduce the epigenetic barriers to iPSC formation. More importantly, KDM8 functions as a co-regulator of the transcription factor SOX2, promoting SOX2's DNA-binding affinity and transcriptional regulation of downstream pluripotency target genes. Accordingly, we propose a novel regulatory framework that uncovers novel mechanisms and functions of KDM8 in cellular reprogramming.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102963"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278843","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 : 2026-07-14Epub Date: 2026-06-11DOI: 10.1016/j.stemcr.2026.102958
Vukasin M Jovanovic, Narisu Narisu, Lori L Bonnycastle, David Castellano, Seungmi Ryu, Ravi Tharakan, Kendall T Mesch, Qiang Chen, Fahrünisa Meryem Betül Erol, Hannah J Glover, Tingfen Yan, Neelam Sinha, Chaitali Sen, Shu Yang, Dvir Blivis, Daniel F Bennett, Giovanni Rosales-Soto, Jason Inman, Pinar Ormanoglu, Christopher A LeClair, Natalie D Shaw, Menghang Xia, Martin Schneider, Erick O Hernandez-Ochoa, Michael R Erdos, Anton Simeonov, Shuibing Chen, Francis S Collins, Claudia A Doege, Carlos A Tristan
{"title":"Scalable hypothalamic neuron differentiation from human pluripotent stem cells suitable for modeling metabolic disorders.","authors":"Vukasin M Jovanovic, Narisu Narisu, Lori L Bonnycastle, David Castellano, Seungmi Ryu, Ravi Tharakan, Kendall T Mesch, Qiang Chen, Fahrünisa Meryem Betül Erol, Hannah J Glover, Tingfen Yan, Neelam Sinha, Chaitali Sen, Shu Yang, Dvir Blivis, Daniel F Bennett, Giovanni Rosales-Soto, Jason Inman, Pinar Ormanoglu, Christopher A LeClair, Natalie D Shaw, Menghang Xia, Martin Schneider, Erick O Hernandez-Ochoa, Michael R Erdos, Anton Simeonov, Shuibing Chen, Francis S Collins, Claudia A Doege, Carlos A Tristan","doi":"10.1016/j.stemcr.2026.102958","DOIUrl":"10.1016/j.stemcr.2026.102958","url":null,"abstract":"<p><p>The hypothalamus, composed of multiple nuclei, is essential for maintaining the body's homeostasis. Within the mediobasal hypothalamus, the arcuate nucleus (ARC) contains key neuronal populations, including appetite-suppressing pro-opiomelanocortin (POMC) neurons that regulate energy and glucose balance. Here, we present a chemically defined, scalable method for differentiating human pluripotent stem cells (hPSCs) into hypothalamic neurons enriched for POMC cells, compatible with robotic cell culture platforms for high-throughput use. Neuronal identity was validated by MERFISH single-cell transcriptomics, RNA-Seq, ATAC-Seq, and comparison to human hypothalamus. The method is robust across multiple hPSC lines, showing consistent induction of ventral diencephalon and hypothalamic markers. Derived neurons display metabolic disease-relevant features, including body mass index (BMI)-associated gene enrichment, and ATAC-Seq identifies potential candidate regulatory regions linked to hypothalamic development and metabolic traits. Functional assays reveal neuronal responses to insulin and the GLP-1 receptor agonist Exendin-4, and transcriptional responses to altered glucose conditions. This platform delivers a physiologically relevant model of human hypothalamic neurons that enables deeper mechanistic and therapeutic studies of metabolic disease.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"102958"},"PeriodicalIF":5.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148228573","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}
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