Hematopoietic stem cell: self-renewal versus differentiation

Abstract

The mammalian blood system, containing more than 10 distinct mature cell types, stands on one specific cell type, hematopoietic stem cell (HSC). Within the system, only HSCs possess the ability of both multipotency and self-renewal. Multipotency is the ability to differentiate into all functional blood cells. Self-renewal is the ability to give rise to HSC itself without differentiation. Since mature blood cells (MBCs) are predominantly short-lived, HSCs continuously provide more differentiated progenitors while properly maintaining the HSC pool size throughout life by precisely balancing self-renewal and differentiation. Thus, understanding the mechanisms of self-renewal and differentiation of HSC has been a central issue. In this review, we focus on the hierarchical structure of the hematopoietic system, the current understanding of microenvironment and molecular cues regulating self-renewal and differentiation of adult HSCs, and the currently emerging systems approaches to understand HSC biology.

Figure 1. Model of the hematopoietic hierarchy

The HSC resides at the top of the hierarchy, and is defined as the cell that has both the self-renewal capacity and the potential to give rise to all hematopoietic cell types (multi-potency). Throughout differentiation, a HSC first loses self-renewal capacity, then loses lineage potential step-by-step as it commits to become a mature functional cell of a certain lineage. The cell surface phenotype of each population is shown for the mouse and human systems. Intermediate precursors between the first lineage committed progenitors and final mature cell, and different subsets of mature B- and T-cells are omitted. In the mouse system, heterogeneity of MPPs has been revealed by differences in cell surface marker phenotypes and functional differences of their subsets discussed. For example, evidence suggests that some of MPPs directly give rise to MEP without passing through CMP (dashed arrow). HSC: hematopoietic stem cell, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, MEP: Megakaryocyte/erythrocyte progenitor, GMP: granulocyte/macrophage progenitor, MkP: Megakaryocyte progenitor, EP: erythrocyte progenitor, GP: granulocyte progenitor, MacP: macrophage progenitor, DC: dendritic cell, NK: natural killer, Lin: lineage markers.