Natural and age-related variation in circulating human hematopoietic stem cells

Abstract

AbstractHematopoietic stem and progenitor cells (HSPCs) are intended to deliver life-long, consistent output. However, with age, we observe changes in blood counts and clonal disorders. Better understanding of inter-individual variation in HSPC behavior is needed to understand the transition from health to age-related hematological disorders. Here we study 360K single circulating HSPCs (CD34+) from 99 healthy individuals together with clinical information and clonal hematopoiesis (CH) profiles to characterize population variability in hematopoiesis. Individuals with CH were linked with reduced frequencies of lymphocyte progenitors and higher RDW. We describe a Lamin-A transcriptional signature across the HSPC spectrum and show it is reduced in CH individuals. We define and estimate HSPC composition bias and an age-related increased S-phase gene signature and show how they form a heterogeneous and multifactorial aging trend in the blood. The new comprehensive model of normal HSPC variation will allow the study of stem cell-related disorders. As a proof of concept, we present methodologies for analyzing myeloid malignancies in comparison to our reference atlas. Together, our data and methodologies shed light on age-related changes in blood counts, CH and can be used to study stem cell-related disorders in the future.