A Growing Population of Harmful Megakaryocyte Progenitors Contribute to Age-Related Thrombosis
Blood clotting relies upon platelets and the reaction of those platelets to circumstances that indicate clotting is required: when suitably provoked platelets adhere to tissue, change shape, and bind to one another to form a clot. Platelets are essentially small slices of cell membrane and cytoplasm, shed by a specialized form of bone marrow cell called a megakaryocyte. Like all complex processes, clotting is impacted by age-related changes in cells and tissue. Platelets become more willing to clot, and can produce inappropriate clotting inside blood vessels, leading to thrombosis. We might ask how much of this problem is innate to platelets versus arising from damage to the vascular endothelium and an altered signaling environment.
In today's open access preprint, researcher suggest that the problem is innate to platelets. The authors provide evidence for a minority population of megakaryocytes to grow in number with age. This population produces overly reactive platelets, and as these problematic platelets grow as a proportion of all platelets, so the risk of inappropriate clotting rises. This is analogous to other similar issues in the production of blood cells and immune cells in the bone marrow, in which aging produces unfavorable shifts in relative numbers. Evidence to date suggests much of this is driven by chronic inflammation, but that is no doubt far from the only mechanism in play.
Distinct routes of cellular production from hematopoietic stem cells (HSCs) have defined our current view of hematopoiesis. Recently, we challenged classical views of platelet generation, demonstrating that megakaryocyte progenitors (MkPs), and ultimately platelets, can be specified via an alternate and additive route of HSC-direct specification specifically during aging. This "shortcut" pathway generates hyperactive platelets likely to contribute to age-related platelet-mediated morbidities.
Here, we used single-cell RNA/CITEseq to demonstrate that these age-unique, non-canonical (nc)MkPs can be prospectively defined and experimentally isolated from wild type mice. Surprisingly, this revealed that a rare population of ncMkPs also exist in young mice. Young and aged ncMkPs are functionally distinct from their canonical (c)MkP counterparts, with aged ncMkPs paradoxically and uniquely exhibiting enhanced survival and platelet generation capacity. We further demonstrate that aged HSCs generate significantly more ncMkPs than their younger counterparts, yet this is accomplished without strict clonal restriction.
Together, these findings reveal significant phenotypic, functional, and aging-dependent heterogeneity among the MkP pool and uncover unique features of megakaryopoiesis throughout life, potentially offering cellular and molecular targets for mitigation of age-related adverse thrombotic events.