Hematopoietic Stem Cell Heterogeneity

Abstract

Hematopoietic stem cells (HSCs) maintain lifelong production of mature blood cells and regenerate the hematopoietic system after cytotoxic injury. Use of expanding cell surface marker panels and advanced functional analyses have revealed the presence of several immunophenotypically different HSC subsets with distinct self-renewal and repopulating capacity and bias toward selective lineage differentiation. This chapter summarizes current understanding of the phenotypic and functional heterogeneity within the HSC pool, with emphasis on the immunophenotypes and functional features of several known HSC subsets, and their roles in steady-state and emergency hematopoiesis, and in aging. The chapter also highlights some of the future research directions to elucidate further the biology and function of different HSC subsets in health and disease states.

Keywords: Hematopoietic stem cellsHematopoiesisHSC subsetsFunctional heterogeneityDifferentiation bias.

Fig. 10.1

Functional features of short-term repopulating HSCs (STR-HSC) and long-term repopulating HSCs (LTR-HSC). (a) LTR-HSCs display long-term self-renewal and repopulating capacity, whereas STR-HSCs exhibit short-term self-renewal and repopulating capacity. (b) During homeostasis, the majority of LTR-HSCs are CD34^neg, and are quiescent and dividing infrequently. In response to stress and injury, dormant HSCs are activated and start to express CD34, and cycle more frequently. Activated HSCs are maintaining themselves and are generating STR-HSCs through asymmetric self-renewal divisions. After restoring homeostasis of the hematopoietic system, activated HSCs return to a quiescent state

Fig. 10.2

Lineage-biased HSC subsets exhibit in vivo lineage differentiation bias. Lineage-balanced HSCs produce balanced amounts of myeloid and lymphoid progeny. Myeloid-biased HSCs exhibit long-term self-renewal capacity and myeloid differentiation bias. Lymphoid-biased HSCs display lymphoid differentiation bias and lower self-renewal capacity and proliferate more frequently. Megakaryocyte-biased HSCs display megakaryocytic/platelet-biased differentiation capacity

Fig. 10.3

Age-induced changes in lineage-biased HSC subsets. (a) In a current model of HSC aging, the subset of My-HSCs expands, but their long-term self-renewal and repopulating capacity are declining. In contrast, the pool of Ly-HSCs is reduced, contributing to reduced lymphopoiesis and decreased output of lymphoid progeny. (b) In an alternative newly proposed model, the numbers of old Ly-HSCs do not change, but their lineage differentiation bias could be switching to myelopoiesis, resulting in decreased output of lymphoid progeny