Lindsey H Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V Nayak, Paulo El Parente, Margaux Sambon, Pablo J Atria, Mohamed A E Ali, Lukasz Witek, Alesha B Castillo, Christopher Y Park, Ralf H Adams, Aristotelis Tsirigos, Sophie M Morgani, Philipp Leucht
{"title":"骨骼干细胞中Notch信号的缺失会随着衰老而增强骨形成。","authors":"Lindsey H Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V Nayak, Paulo El Parente, Margaux Sambon, Pablo J Atria, Mohamed A E Ali, Lukasz Witek, Alesha B Castillo, Christopher Y Park, Ralf H Adams, Aristotelis Tsirigos, Sophie M Morgani, Philipp Leucht","doi":"10.1038/s41413-023-00283-8","DOIUrl":null,"url":null,"abstract":"<p><p>Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522593/pdf/","citationCount":"0","resultStr":"{\"title\":\"Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.\",\"authors\":\"Lindsey H Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V Nayak, Paulo El Parente, Margaux Sambon, Pablo J Atria, Mohamed A E Ali, Lukasz Witek, Alesha B Castillo, Christopher Y Park, Ralf H Adams, Aristotelis Tsirigos, Sophie M Morgani, Philipp Leucht\",\"doi\":\"10.1038/s41413-023-00283-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.</p>\",\"PeriodicalId\":9134,\"journal\":{\"name\":\"Bone Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":14.3000,\"publicationDate\":\"2023-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522593/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bone Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41413-023-00283-8\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bone Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41413-023-00283-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.
Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.
期刊介绍:
Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.