In certain highly regenerative animals, cellular dedifferentiation occurs after injury, allowing specialized cells to become progenitor cells for regeneration. However, this capacity is restricted in human cells due to reduced plasticity. Here, we introduce a chemical-induced dedifferentiation approach that reverts the differentiated cells to a progenitor-like state, conferring the features of human limb bud cells from human adult somatic cells. These chemically induced human limb-bud-like progenitors (hCiLBP cells) show a high degree of transcriptomic similarity to human embryonic limb bud progenitors. Importantly, we established culture conditions that allow hCiLBP cells to undergo extensive expansion while maintaining population homogeneity and long-term self-renewal capacity. Moreover, hCiLBP cells exhibit increased osteochondrogenic differentiation ability, providing an innovative platform for generation of skeletal lineage cell types. These results highlight a potential therapeutic approach for repairing damaged human tissues through reversal of developmental pathways from mature cells to expandable progenitor cells.
{"title":"Generation of human expandable limb-bud-like progenitors via chemically induced dedifferentiation","authors":"Jialiang Zhu, Xinxing Zhong, Huanjing He, Jingxiao Cao, Zhengyang Zhou, Jiebin Dong, Honggang Li, Anqi Zhang, Yulin Lyu, Cheng Li, Jingyang Guan, Hongkui Deng","doi":"10.1016/j.stem.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.stem.2024.10.001","url":null,"abstract":"In certain highly regenerative animals, cellular dedifferentiation occurs after injury, allowing specialized cells to become progenitor cells for regeneration. However, this capacity is restricted in human cells due to reduced plasticity. Here, we introduce a chemical-induced dedifferentiation approach that reverts the differentiated cells to a progenitor-like state, conferring the features of human limb bud cells from human adult somatic cells. These chemically induced human limb-bud-like progenitors (hCiLBP cells) show a high degree of transcriptomic similarity to human embryonic limb bud progenitors. Importantly, we established culture conditions that allow hCiLBP cells to undergo extensive expansion while maintaining population homogeneity and long-term self-renewal capacity. Moreover, hCiLBP cells exhibit increased osteochondrogenic differentiation ability, providing an innovative platform for generation of skeletal lineage cell types. These results highlight a potential therapeutic approach for repairing damaged human tissues through reversal of developmental pathways from mature cells to expandable progenitor cells.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486507","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}
Pub Date : 2024-10-22DOI: 10.1016/j.stem.2024.09.018
Rong Mou, Junkai Ma, Xuan Ju, Yixin Wu, Qiuli Chen, Jinglin Li, Tongyao Shang, Siying Chen, Yue Yang, Yue Li, Kaosheng Lv, Xuequn Chen, Qi Zhang, Tingbo Liang, Ye Feng, Xinjiang Lu
Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.
{"title":"Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice","authors":"Rong Mou, Junkai Ma, Xuan Ju, Yixin Wu, Qiuli Chen, Jinglin Li, Tongyao Shang, Siying Chen, Yue Yang, Yue Li, Kaosheng Lv, Xuequn Chen, Qi Zhang, Tingbo Liang, Ye Feng, Xinjiang Lu","doi":"10.1016/j.stem.2024.09.018","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.018","url":null,"abstract":"Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6C<sup>hi</sup> monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"124 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486550","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}
Pub Date : 2024-10-21DOI: 10.1016/j.stem.2024.09.014
Rosana-Bristena Ionescu, Alexandra M. Nicaise, Julie A. Reisz, Eleanor C. Williams, Pranathi Prasad, Cory M. Willis, Madalena B.C. Simões-Abade, Linda Sbarro, Monika Dzieciatkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti-Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D’Alessandro, Stefano Pluchino
Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.
{"title":"Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis","authors":"Rosana-Bristena Ionescu, Alexandra M. Nicaise, Julie A. Reisz, Eleanor C. Williams, Pranathi Prasad, Cory M. Willis, Madalena B.C. Simões-Abade, Linda Sbarro, Monika Dzieciatkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti-Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D’Alessandro, Stefano Pluchino","doi":"10.1016/j.stem.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.014","url":null,"abstract":"Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype <em>in vitro</em>. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"65 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452398","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}
Pub Date : 2024-10-21DOI: 10.1016/j.stem.2024.09.016
Jiapeng Yang, Peng Wang, Yu Zhang, Man Zhang, Qian Sun, Huiyan Chen, Liang Dong, Zhiqin Chu, Bin Xue, Wouter David Hoff, Changsheng Zhao, Wei Wang, Qiang Wei, Yi Cao
Cells use traction forces to sense mechanical cues in their environment. While the molecular clutch model effectively explains how cells exert more forces on stiffer substrates, it falls short in addressing their adaptation to dynamic mechanical fluctuations prevalent in tissues and organs. Here, using hydrogel with photo-responsive rigidity, we show that cells’ response to rigidity changes is frequency dependent. Strikingly, at certain frequencies, cellular traction forces exceed those on static substrates 4-fold stiffer, challenging the established molecular clutch model. We discover that the discrepancy between the rapid adaptation of traction forces and the slower deactivation of mechanotransduction signaling proteins results in their accumulation, thereby enhancing long-term cellular traction in dynamic settings. Consequently, we propose a new model that melds immediate mechanosensing with extended mechanical signaling. Our study underscores the significance of dynamic rigidity in the development of synthetic biomaterials, emphasizing the importance of considering both immediate and prolonged cellular responses.
{"title":"Photo-tunable hydrogels reveal cellular sensing of rapid rigidity changes through the accumulation of mechanical signaling molecules","authors":"Jiapeng Yang, Peng Wang, Yu Zhang, Man Zhang, Qian Sun, Huiyan Chen, Liang Dong, Zhiqin Chu, Bin Xue, Wouter David Hoff, Changsheng Zhao, Wei Wang, Qiang Wei, Yi Cao","doi":"10.1016/j.stem.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.016","url":null,"abstract":"Cells use traction forces to sense mechanical cues in their environment. While the molecular clutch model effectively explains how cells exert more forces on stiffer substrates, it falls short in addressing their adaptation to dynamic mechanical fluctuations prevalent in tissues and organs. Here, using hydrogel with photo-responsive rigidity, we show that cells’ response to rigidity changes is frequency dependent. Strikingly, at certain frequencies, cellular traction forces exceed those on static substrates 4-fold stiffer, challenging the established molecular clutch model. We discover that the discrepancy between the rapid adaptation of traction forces and the slower deactivation of mechanotransduction signaling proteins results in their accumulation, thereby enhancing long-term cellular traction in dynamic settings. Consequently, we propose a new model that melds immediate mechanosensing with extended mechanical signaling. Our study underscores the significance of dynamic rigidity in the development of synthetic biomaterials, emphasizing the importance of considering both immediate and prolonged cellular responses.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"223 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452396","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}
Pub Date : 2024-10-18DOI: 10.1016/j.stem.2024.09.013
Yi-Ru Shen, Sofia Zaballa, Xavier Bech, Anna Sancho-Balsells, Irene Rodríguez-Navarro, Carmen Cifuentes-Díaz, Gönül Seyit-Bremer, Seung Hee Chun, Tobias Straub, Jordi Abante, Iñaki Merino-Valverde, Laia Richart, Vipul Gupta, Hao-Yi Li, Ivan Ballasch, Noelia Alcázar, Jordi Alberch, Josep M. Canals, Maria Abad, Manuel Serrano, Daniel del Toro
Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatiotemporal manner in two different scenarios: brain development and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF induction led to progenitor expansion, an increased number of upper cortical neurons and glia, and enhanced motor and social behavior in adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimer’s disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. These results highlight the powerful impact of YFs on neural proliferation and their potential use in brain disorders.
{"title":"Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming","authors":"Yi-Ru Shen, Sofia Zaballa, Xavier Bech, Anna Sancho-Balsells, Irene Rodríguez-Navarro, Carmen Cifuentes-Díaz, Gönül Seyit-Bremer, Seung Hee Chun, Tobias Straub, Jordi Abante, Iñaki Merino-Valverde, Laia Richart, Vipul Gupta, Hao-Yi Li, Ivan Ballasch, Noelia Alcázar, Jordi Alberch, Josep M. Canals, Maria Abad, Manuel Serrano, Daniel del Toro","doi":"10.1016/j.stem.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.013","url":null,"abstract":"Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatiotemporal manner in two different scenarios: brain development and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF induction led to progenitor expansion, an increased number of upper cortical neurons and glia, and enhanced motor and social behavior in adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimer’s disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. These results highlight the powerful impact of YFs on neural proliferation and their potential use in brain disorders.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"58 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448371","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}
Pub Date : 2024-10-18DOI: 10.1016/j.stem.2024.09.015
Yawen Li, Yalin He, Qi Zheng, Jiazhu Zhang, Xinwen Pan, Xi Zhang, Huairui Yuan, Guangchuan Wang, Xin Liu, Xiaolong Zhou, Xueliang Zhu, Tao Ren, Pengfei Sui
Basal cells (BCs) are the progenitor cells responsible for tracheal epithelium integrity. Here, we demonstrate that mitochondrial pyruvate carriers (MPCs) act as metabolic checkpoints that are essential for BC fate decision. Inhibition of MPCs enables long-term expansion of BCs from both mice and humans. Genetic inactivation of Mpc2 in mice leads to BC hyperplasia and reduced ciliated cells during homeostasis, as well as delayed epithelial regeneration and accumulation of intermediate cells following injury. Mechanistically, MPC2 links glycolysis to ATP citrate lyase (ACLY)-dependent cytosolic acetyl-coenzyme A (CoA) generation, which is required for the epigenetic control of differentiation-related gene transcription. Modulating this metabolic-epigenetic axis partially rescues Yes-associated protein (YAP)-dysfunction-induced changes in BCs. Importantly, exogenous citrate promotes the differentiation of BCs from chronic obstructive lung disease (COPD) patients. Thus, beyond demonstrating the role of pyruvate metabolism in BC fate decision, our study suggests that targeting pyruvate-citrate metabolism may serve as a potential strategy to rectify abnormal BC behavior in lung diseases.
基底细胞（BC）是负责气管上皮完整性的祖细胞。在这里，我们证明了线粒体丙酮酸载体（MPCs）作为新陈代谢的检查点对BC命运的决定至关重要。抑制线粒体丙酮酸载体可使小鼠和人类的BC长期扩增。小鼠 Mpc2 基因失活会导致 BC 增生和纤毛细胞减少，以及上皮再生延迟和损伤后中间细胞堆积。从机理上讲，MPC2 将糖酵解与依赖于细胞膜乙酰辅酶 A（CoA）生成的柠檬酸ATP裂解酶（ACLY）联系起来，而乙酰辅酶 A 是分化相关基因转录的表观遗传控制所必需的。调节这一代谢-表观遗传轴可部分缓解Yes相关蛋白（YAP）功能障碍诱导的BC变化。重要的是，外源性柠檬酸盐能促进慢性阻塞性肺病（COPD）患者 BCs 的分化。因此，除了证明丙酮酸代谢在BC命运决定中的作用外，我们的研究还表明，靶向丙酮酸-柠檬酸代谢可能是纠正肺部疾病中异常BC行为的一种潜在策略。
{"title":"Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming","authors":"Yawen Li, Yalin He, Qi Zheng, Jiazhu Zhang, Xinwen Pan, Xi Zhang, Huairui Yuan, Guangchuan Wang, Xin Liu, Xiaolong Zhou, Xueliang Zhu, Tao Ren, Pengfei Sui","doi":"10.1016/j.stem.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.015","url":null,"abstract":"Basal cells (BCs) are the progenitor cells responsible for tracheal epithelium integrity. Here, we demonstrate that mitochondrial pyruvate carriers (MPCs) act as metabolic checkpoints that are essential for BC fate decision. Inhibition of MPCs enables long-term expansion of BCs from both mice and humans. Genetic inactivation of <em>Mpc2</em> in mice leads to BC hyperplasia and reduced ciliated cells during homeostasis, as well as delayed epithelial regeneration and accumulation of intermediate cells following injury. Mechanistically, MPC2 links glycolysis to ATP citrate lyase (ACLY)-dependent cytosolic acetyl-coenzyme A (CoA) generation, which is required for the epigenetic control of differentiation-related gene transcription. Modulating this metabolic-epigenetic axis partially rescues Yes-associated protein (YAP)-dysfunction-induced changes in BCs. Importantly, exogenous citrate promotes the differentiation of BCs from chronic obstructive lung disease (COPD) patients. Thus, beyond demonstrating the role of pyruvate metabolism in BC fate decision, our study suggests that targeting pyruvate-citrate metabolism may serve as a potential strategy to rectify abnormal BC behavior in lung diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448382","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}
Pub Date : 2024-10-15DOI: 10.1016/j.stem.2024.09.010
Taylor S. Mills, Bailee Kain, Matt A. Burchill, Etienne Danis, Erin D. Lucas, Rachel Culp-Hill, Courtney M. Cowan, Wolfgang E. Schleicher, Sweta B. Patel, Brandon T. Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A. Jirón Tamburini, James R. Roede, Angelo D’Alessandro, Katherine Y. King, Eric M. Pietras
Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.
在此，我们研究了长期造血干细胞（HSCsLT）在慢性自身免疫性疾病中对训练免疫（TI）的贡献。利用系统性红斑狼疮（SLE）小鼠模型，我们发现来自自身免疫性小鼠的骨髓源性巨噬细胞（BMDMs）表现出TI的标志性特征，包括分枝杆菌杀伤力增强和炎性细胞因子产生，而这些特征在机理上与糖代谢增强有关。我们的研究表明，来自自身免疫小鼠的造血干细胞构成了一个可移植的、长期的巨噬细胞储库，这些巨噬细胞具有 TI 的功能特性。然而，这些 BMDMs 表现出糖酵解活性和代谢基因染色质可及性的降低，同时与 TI 相关的转录调控因子的表达仍保持升高。因此，暴露于自身免疫炎症的造血干细胞可产生巨噬细胞，其中 TI 的功能和代谢特性是分离的。我们的数据支持这样一个模型：TI 的特征是一系列分子和代谢状态驱动免疫功能增强。
{"title":"A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice","authors":"Taylor S. Mills, Bailee Kain, Matt A. Burchill, Etienne Danis, Erin D. Lucas, Rachel Culp-Hill, Courtney M. Cowan, Wolfgang E. Schleicher, Sweta B. Patel, Brandon T. Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A. Jirón Tamburini, James R. Roede, Angelo D’Alessandro, Katherine Y. King, Eric M. Pietras","doi":"10.1016/j.stem.2024.09.010","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.010","url":null,"abstract":"Here, we investigate the contribution of long-term hematopoietic stem cells (HSCs<sup>LT</sup>) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased <em>Mycobacterium avium</em> killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"229 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436340","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}
Pub Date : 2024-10-14DOI: 10.1016/j.stem.2024.09.011
Adriana Migliorini, Sabrina Ge, Michael H. Atkins, Amanda Oakie, Rangarajan Sambathkumar, Gregory Kent, Haiyang Huang, Angel Sing, Conan Chua, Adam J. Gehring, Gordon M. Keller, Faiyaz Notta, Maria Cristina Nostro
Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.
{"title":"Embryonic macrophages support endocrine commitment during human pancreatic differentiation","authors":"Adriana Migliorini, Sabrina Ge, Michael H. Atkins, Amanda Oakie, Rangarajan Sambathkumar, Gregory Kent, Haiyang Huang, Angel Sing, Conan Chua, Adam J. Gehring, Gordon M. Keller, Faiyaz Notta, Maria Cristina Nostro","doi":"10.1016/j.stem.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.011","url":null,"abstract":"Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction <em>in vitro</em>. Here, we show that macrophages support the differentiation and viability of endocrine cells <em>in vitro</em> and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"11 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431233","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}
Pub Date : 2024-10-03DOI: 10.1016/j.stem.2024.09.007
Laertis Ikonomou, Megan Munsie, Carl Power, Douglas Sipp, Leigh Turner, John E.J. Rasko
The rapid proliferation of businesses engaged in direct-to-consumer advertising of unproven stem cell interventions has raised troubling questions about whether government bodies can regulate this health market effectively. Recent developments in Australia and Canada suggest that such fears are unfounded and that targeted regulatory action can have meaningful effects.
{"title":"Effective regulatory responses to predatory stem cell markets in Australia and Canada","authors":"Laertis Ikonomou, Megan Munsie, Carl Power, Douglas Sipp, Leigh Turner, John E.J. Rasko","doi":"10.1016/j.stem.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.007","url":null,"abstract":"The rapid proliferation of businesses engaged in direct-to-consumer advertising of unproven stem cell interventions has raised troubling questions about whether government bodies can regulate this health market effectively. Recent developments in Australia and Canada suggest that such fears are unfounded and that targeted regulatory action can have meaningful effects.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369163","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}
Pub Date : 2024-10-03DOI: 10.1016/j.stem.2024.09.006
Claudia R. Ball, Stefan Fröhling
Drug sensitivity profiling in patient-derived tumor models offers new hope for improving outcomes in cancers lacking effective therapies. Al Shihabi et al.1 demonstrate that short-term cultures from bone and soft tissue sarcomas enable clinically meaningful screening of multiple drugs and combinations, marking a significant advance in personalized care for these high-risk diseases.
{"title":"Let’s get functional: Drug sensitivity profiling to enable precision sarcoma medicine","authors":"Claudia R. Ball, Stefan Fröhling","doi":"10.1016/j.stem.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.006","url":null,"abstract":"Drug sensitivity profiling in patient-derived tumor models offers new hope for improving outcomes in cancers lacking effective therapies. Al Shihabi et al.<span><span><sup>1</sup></span></span> demonstrate that short-term cultures from bone and soft tissue sarcomas enable clinically meaningful screening of multiple drugs and combinations, marking a significant advance in personalized care for these high-risk diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"24 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369161","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}
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