UC Santa Cruz

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Hematopoietic stem and progenitor cells give rise to platelets, but their contributions to variable thrombopoiesis and hemostasis throughout life remain unclear. We performed heterochronic and isochronic hematopoietic stem cell (HSC) transplants followed by quantitative analysis of cell reconstitution. While young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) and platelets in old mice, transplanted old HSCs were inefficient in regenerative hematopoiesis, including thrombopoiesis. Hence, we performed functional analysis of young and old MkPs that demonstrated the unmistakably greater regenerative capacity of old MkPs compared to young MkPs. These data uncover that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging. Using an unequivocal genetic lineage tracing mouse model, we then made the remarkable discovery of a platelet differentiation pathway arising from HSCs and that is unique to aging. This age-specific pathway is progressively propagated over time and operates as an additional layer in parallel with canonical platelet production, yielding an additional MkP/platelet population that exists only in old mice. It is also independent from all other hematopoietic lineages, including erythropoiesis. Our experiments to understand the underlying mechanisms of age-specific platelet pathway uncover that the resulting two populations of MkPs are molecularly and functionally distinct, and that were also evident and age-dependent in humans. Surprisingly, the age-specific MkP population exclusively harbor the elevated thrombopoietic potential we observed in old MkPs, exhibited by their strikingly profound capacity to engraft, expand, and restore platelets upon transplantation. In contrast, the canonically derived old MkPs displayed inefficient platelet potential similar to young MkPs. Consistent with increased thrombotic incidence upon aging, the two pools of co-existing platelets contribute to age-related thrombocytosis and dramatically increased thrombosis in vivo. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation.