Daozheng Yang, Natalia Skinder, Yun-Ruei Kao, Jiahao Chen, Victor Thiruthuvanathan, Arthur Flohr Svendsen, Chi Zhang, Bertien Dethmers-Ausema, Ellen Weersing, Maria Maryanovich, Britta Will, Gerald de Haan
{"title":"Aberrant engagement of P-selectin drives hematopoietic stem cell aging in mice.","authors":"Daozheng Yang, Natalia Skinder, Yun-Ruei Kao, Jiahao Chen, Victor Thiruthuvanathan, Arthur Flohr Svendsen, Chi Zhang, Bertien Dethmers-Ausema, Ellen Weersing, Maria Maryanovich, Britta Will, Gerald de Haan","doi":"10.1038/s43587-025-00880-8","DOIUrl":null,"url":null,"abstract":"<p><p>During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1010-1024"},"PeriodicalIF":17.0000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature aging","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s43587-025-00880-8","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/23 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.