Yang Daozheng, Skinder Natalia, Kao Yun-Ruei, Chen Jiahao, Thiruthuvanathan Victor, Flohr Svendsen Arthur, Zhang Chi, Dethmers-Ausema Bertien, Weersing Ellen, Maryanovich Maria, Will Britta, de Haan Gerald
European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Nat Aging. 2025 May 23. doi: 10.1038/s43587-025-00880-8.
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.
在衰老过程中，造血干细胞（HSC）功能逐渐衰退，这会导致血细胞生成和再生减少。这项研究发现，在小鼠中，由促炎环境驱动的大部分衰老造血干细胞中，P-选择素（由Selp编码的CD62P）的细胞表面表达增加。值得注意的是，P-选择素的表达在分子和功能上对衰老造血干细胞库进行了二分；呈现高丰度P-选择素的干细胞具有衰老相关基因表达程序的特征，并且在再生应激时其重建能力降低。在年轻造血干细胞中异位表达Selp足以损害长期重建潜力并损害红细胞生成。从机制上讲，我们发现其主要配体P-选择素糖蛋白配体-1激活P-选择素受体可抑制衰老相关基因表达，相反，缺乏P-选择素信号会导致造血干细胞过早衰老。总的来说，我们的研究揭示了P-选择素参与调节造血干细胞再生以及在受到干扰时驱动干细胞衰老的功能作用。
