3006 – FUNCTIONALLY DISTINCT MEGAKARYOCYTE PROGENITOR POPULATIONS DIFFERENTIALLY CONTRIBUTE TO HEMATOPOIESIS THROUGHOUT LIFE AND DURING PHYSIOLOGICAL AND INDUCED CHRONIC INFLAMMATION

Abstract

Hematopoiesis changes upon aging, including expansion of hematopoietic stem cells (HSCs) and megakaryocyte progenitors (MkPs), which undergo changes in phenotype and function. Platelets, the progeny of MkPs, also undergo age-related alterations that drive inflammation and cardiovascular and thrombotic disease; major health concerns. We discovered a non-canonical (ncMkP) population that specifically expands upon aging. Compared to their canonical (cMkP) counterparts, ncMkPs exhibit increased expansion and survival with age. Upon transplantation and serial blood assessment, both young and old cMkPs, and young ncMkPs, contributed to similar levels of platelet formation. In contrast, aged ncMkPs specifically produced greater platelet output. The progressive increase in ncMkPs with age appears to be, in part, originating from HSCs as in vitro generation of ncMkPs was significantly enhanced by aged compared to young HSCs. Further, single-cell functional analysis revealed that this was not driven by individual HSC clones, a finding substantiated by single-cell RNA sequencing of young and old bone marrow (BM). Progressively increasing, chronic inflammation is thought to be a driver of aging. Inducing chronic inflammation in young mice partially phenocopies known features of aged mice, including altered platelet output and expanded HSC numbers, implicating its role in influencing age-related platelet production. Direct assessment of inflammatory modulation of young and old HSCs, cMkPs, and ncMkPs via in vitro culture revealed distinct age- and population-specific responses, uncovering surprisingly distinct and differential roles for direct inflammatory reprogramming. These new data provide mechanistic insight to cell-based causes of aging-related adverse thrombotic events and may offer targets for mitigation and rejuvenation.