Cell stem cellPub Date : 2024-09-03DOI: 10.1016/j.stem.2024.08.005
Zan Lv, Zixin Liu, Kuo Liu, Xiuyu Lin, Wenjuan Pu, Yan Li, Huan Zhao, Ying Xi, Pengfei Sui, Andrew E. Vaughan, Astrid Gillich, Bin Zhou
{"title":"Alveolar regeneration by airway secretory-cell-derived p63+ progenitors","authors":"Zan Lv, Zixin Liu, Kuo Liu, Xiuyu Lin, Wenjuan Pu, Yan Li, Huan Zhao, Ying Xi, Pengfei Sui, Andrew E. Vaughan, Astrid Gillich, Bin Zhou","doi":"10.1016/j.stem.2024.08.005","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.005","url":null,"abstract":"<p>Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. Unraveling the origin and fate of injury-induced progenitors is crucial for elucidating lung repair mechanisms. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced mouse lung injury. Single-cell RNA sequencing and clonal analysis reveal that these p63<sup>+</sup> progenitors proliferate rapidly and differentiate into alveolar type 1 and type 2 cells through different trajectories. Dual recombinase-mediated sequential genetic-lineage tracing demonstrates that p63<sup>+</sup> progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is essential for efficient alveolar regeneration from secretory cells post injury. Our study identifies secretory-cell-derived p63<sup>+</sup> progenitors as contributors to alveolar repair, suggesting a potential therapeutic avenue for lung regeneration following injury.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"48 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123910","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 : 2024-09-03DOI: 10.1016/j.stem.2024.08.007
Liuliu Yang, Yuling Han, Tuo Zhang, Xue Dong, Jian Ge, Aadita Roy, Jiajun Zhu, Tiankun Lu, J. Jeya Vandana, Neranjan de Silva, Catherine C. Robertson, Jenny Z. Xiang, Chendong Pan, Yanjie Sun, Jianwen Que, Todd Evans, Chengyang Liu, Wei Wang, Ali Naji, Stephen C.J. Parker, Shuibing Chen
{"title":"Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection","authors":"Liuliu Yang, Yuling Han, Tuo Zhang, Xue Dong, Jian Ge, Aadita Roy, Jiajun Zhu, Tiankun Lu, J. Jeya Vandana, Neranjan de Silva, Catherine C. Robertson, Jenny Z. Xiang, Chendong Pan, Yanjie Sun, Jianwen Que, Todd Evans, Chengyang Liu, Wei Wang, Ali Naji, Stephen C.J. Parker, Shuibing Chen","doi":"10.1016/j.stem.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.007","url":null,"abstract":"<p>There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single-cell RNA sequencing (scRNA-seq) analysis of human islets exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory-macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared with separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory-macrophage-mediated β cell pyroptosis. This study established hPSC-derived VMI organoids as a valuable tool for studying immune-cell-mediated host damage and uncovered the mechanism of β cell damage during viral exposure.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"149 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123926","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 : 2024-09-03DOI: 10.1016/j.stem.2024.08.006
Dongchang Zhao, Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, Arvind Rao, Pavan Reddy
{"title":"Inflammation-induced epigenetic imprinting regulates intestinal stem cells","authors":"Dongchang Zhao, Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, Arvind Rao, Pavan Reddy","doi":"10.1016/j.stem.2024.08.006","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.006","url":null,"abstract":"<p>It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5<sup>+</sup> ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and <em>in vivo</em> models, we found that Lgr5<sup>+</sup> ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate <em>ex vivo</em> in serial organoid cultures and also <em>in vivo</em> following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for <em>in vivo</em> regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123911","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 : 2024-08-28DOI: 10.1016/j.stem.2024.08.004
{"title":"Generation of human region-specific brain organoids with medullary spinal trigeminal nuclei","authors":"","doi":"10.1016/j.stem.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.004","url":null,"abstract":"Brain organoids with nucleus-specific identities provide unique platforms for studying human brain development and diseases at a finer resolution. Des…","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"28 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090517","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 : 2024-08-23DOI: 10.1016/j.stem.2024.08.001
Le Xu, Chunting Tan, Justinn Barr, Nicole Talaba, Jamie Verheyden, Ji Sun Chin, Samvel Gaboyan, Nikita Kasaraneni, Ruth M. Elgamal, Kyle J. Gaulton, Grace Lin, Kamyar Afshar, Eugene Golts, Angela Meier, Laura E. Crotty Alexander, Zea Borok, Yufeng Shen, Wendy K. Chung, David J. McCulley, Xin Sun
{"title":"Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells","authors":"Le Xu, Chunting Tan, Justinn Barr, Nicole Talaba, Jamie Verheyden, Ji Sun Chin, Samvel Gaboyan, Nikita Kasaraneni, Ruth M. Elgamal, Kyle J. Gaulton, Grace Lin, Kamyar Afshar, Eugene Golts, Angela Meier, Laura E. Crotty Alexander, Zea Borok, Yufeng Shen, Wendy K. Chung, David J. McCulley, Xin Sun","doi":"10.1016/j.stem.2024.08.001","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.001","url":null,"abstract":"<p>While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene <em>Lonp1</em> led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of <em>Bok</em>, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"42 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043073","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 : 2024-08-23DOI: 10.1016/j.stem.2024.07.009
Changhong Du, Chaonan Liu, Kuan Yu, Shuzhen Zhang, Zeyu Fu, Xinliang Chen, Weinian Liao, Jun Chen, Yimin Zhang, Xinmiao Wang, Mo Chen, Fang Chen, Mingqiang Shen, Cheng Wang, Shilei Chen, Song Wang, Junping Wang
{"title":"Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury","authors":"Changhong Du, Chaonan Liu, Kuan Yu, Shuzhen Zhang, Zeyu Fu, Xinliang Chen, Weinian Liao, Jun Chen, Yimin Zhang, Xinmiao Wang, Mo Chen, Fang Chen, Mingqiang Shen, Cheng Wang, Shilei Chen, Song Wang, Junping Wang","doi":"10.1016/j.stem.2024.07.009","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.009","url":null,"abstract":"<p>Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"37 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043120","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":"Incompatibility in cell adhesion constitutes a barrier to interspecies chimerism","authors":"Emily Ballard, Masahiro Sakurai, Leqian Yu, Lizhong Liu, Seiya Oura, Jia Huang, Jun Wu","doi":"10.1016/j.stem.2024.07.010","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.010","url":null,"abstract":"<p>Interspecies blastocyst complementation holds great potential to address the global shortage of transplantable organs by growing human organs in animals. However, a major challenge in this approach is the limited chimerism of human cells in evolutionarily distant animal hosts due to various xenogeneic barriers. Here, we reveal that human pluripotent stem cells (PSCs) struggle to adhere to animal PSCs. To overcome this barrier, we developed a synthetic biology strategy that leverages nanobody-antigen interactions to enhance interspecies cell adhesion. We engineered cells to express nanobodies and their corresponding antigens on their outer membranes, significantly improving adhesion between different species’ PSCs during <em>in vitro</em> assays and increasing the chimerism of human PSCs in mouse embryos. Studying and manipulating interspecies pluripotent cell adhesion will provide valuable insights into cell interaction dynamics during chimera formation and early embryogenesis.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"18 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043072","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 : 2024-08-14DOI: 10.1016/j.stem.2024.07.006
{"title":"A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development","authors":"","doi":"10.1016/j.stem.2024.07.006","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.006","url":null,"abstract":"<p>Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific <em>ERVH48-1</em> (<em>SUPYN</em>/Suppressyn). <em>ERVH48-1</em> encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of <em>ERVH48-1</em> led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/β-catenin signaling. Knockdown of <em>SFRP2</em> or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how <em>ERVH48-1</em> modulates WNT/β-catenin signaling and cell type commitment in somatic development.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"40 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981009","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 : 2024-08-02DOI: 10.1016/j.stem.2024.07.004
{"title":"Sustained amphiregulin expression in intermediate alveolar stem cells drives progressive fibrosis","authors":"","doi":"10.1016/j.stem.2024.07.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.004","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"48 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877740","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 : 2024-08-01DOI: 10.1016/j.stem.2024.07.001
{"title":"Macrophages: A missing key in cardiac tissue engineering for sustained vascularization","authors":"","doi":"10.1016/j.stem.2024.07.001","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.001","url":null,"abstract":"<p>Macrophages regulate angiogenesis, repair, conduction, and homeostasis in heart tissue. Landau et al.<span><span><sup>1</sup></span></span> demonstrate that incorporating primitive macrophages into engineered heart tissues significantly promotes long-term vascularization and cardiac maturation. This advance demonstrates the importance of resident immune-vascular microenvironments in cardiac tissue engineering, marking an important step forward for heart-on-chip technologies.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141862433","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}