Poscablo, D. | Search bioRxiv

bioRxiv2021

Megakaryocyte Progenitor Cell Function is Enhanced Upon Aging Despite the Functional Decline of Aged Hematopoietic Stem Cells

Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic 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) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared to young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging. HIGHLIGHTSO_LIFrequencies and total cell numbers of HSCs and MkPs were increased upon aging C_LIO_LIReconstitution deficit by old HSCs was observed by chimerism and absolute cell numbers C_LIO_LIYoung HSCs did not have competitive advantage over old HSCs in aged recipient mice C_LIO_LIOld MkPs display remarkable capacity to engraft, expand, and reconstitute platelets C_LIO_LIAging is associated with changes in MkP genome-wide expression signatures C_LI

cell biology↗

bioRxiv2020

Interleukin 7 receptor (IL7R) is required for myeloid cell homeostasis and reconstitution by hematopoietic stem cells

Respiratory diseases are a leading cause of death worldwide, with highly varied vulnerability to disease between individuals. The underlying reasons of disease susceptibility are unknown, but often include a variable immune response in lungs. Recently, we identified a surprising novel role of the interleukin 7 receptor (IL7R), a primarily lymphoid-associated regulator, in fetal-specified, lung-resident macrophage development. Here, we report that traditional, hematopoietic stem cell-derived myeloid cells in the adult lung, peripheral blood, and bone marrow also depend on IL7R expression. Using single and double germline knockout models, we found that eosinophil numbers were reduced upon deletion of IL7R. We then employed two Cre recombinase models in lineage tracing experiments to test whether these cells developed through an IL7R+ pathway. Despite the impact of IL7R deletion, IL7R-Cre labeled only a minimal fraction of eosinophils. We therefore examined the intrinsic versus extrinsic requirement for IL7R in the production of eosinophils using reciprocal hematopoietic stem cell transplantation assays. These assays revealed that extrinsic, but not eosinophil-intrinsic, IL7R is required for eosinophil reconstitution by HSCs in the adult lung. To determine which external factors may be influencing eosinophil development and survival, we performed a cytokine array analysis between wild-type and IL7R-deficient mice and found several differentially regulated proteins. These findings expand upon our previous publication that IL7R is required not only for proper lymphoid cell development and homeostasis, but also for myeloid cell homeostasis in tissues. HighlightsO_LILoss of IL7R resulted in significantly fewer eosinophils in adult mice C_LIO_LIIL7R-Cre lineage tracing revealed minimal labeling of eosinophils C_LIO_LIIL7R-deficient HSCs robustly reconstituted eosinophils in a WT host C_LIO_LIWT HSCs failed to fully reconstitute eosinophils in IL7R-/- hosts C_LIO_LISeveral cytokines are differentially expressed in WT and IL7R-deficient mice C_LI

immunology↗