Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

Abstract

The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis.

Keywords: aging; childhood leukemias; clonal hematopoiesis of indeterminate potential; development; hematopoietic stem cells; inflamm-aging; metabolism; single-cell transcriptomics.

Figure 1

Incidence rates for hematological malignancies by age at diagnosis in the USA from 2014 to 2018 (https://seer.cancer.gov; accessed 28 November 2021) expressed per 100,000 individuals per annum. (A) Total cases. (B) Cases in A broken down into hematological malignancy subtypes. (C,D) Incidence of ALL, AML and Hodgkin lymphoma from birth to age 49 and 85+ respectively.

Figure 2

Relative (approximate %) incidence of subtypes (identified in order from top to bottom of each graph by the relevant gene fusions, gene rearrangements or aneuploidy) of pediatric B-ALL data stratified into low, moderate and high risk categories,.and adapted from the St. Jude Total Therapy Study XVI data described by Inaba and Pui [130].