1. An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis.
- Author
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Poscablo DM, Worthington AK, Smith-Berdan S, Rommel MGE, Manso BA, Adili R, Mok L, Reggiardo RE, Cool T, Mogharrab R, Myers J, Dahmen S, Medina P, Beaudin AE, Boyer SW, Holinstat M, Jonsson VD, and Forsberg EC
- Subjects
- Animals, Mice, Humans, Megakaryocytes metabolism, Mice, Inbred C57BL, Megakaryocyte Progenitor Cells metabolism, Male, Hematopoietic Stem Cells metabolism, Blood Platelets metabolism, Thrombosis pathology, Thrombosis metabolism, Cell Differentiation, Aging
- Abstract
Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitors. The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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