Causes and Consequences of Hematopoietic Stem Cell Heterogeneity

Abstract

Blood and immune cells derive from multipotent hematopoietic stem cells (HSCs). Classically, stem and progenitor populations have been considered discrete homogeneous populations. However, recent technological advances have revealed significant HSC heterogeneity, with evidence for early HSC lineage segregation and the presence of lineage-biased HSCs and lineage-restricted progenitors within the HSC compartment. These and other findings challenge many aspects of the classical view of HSC biology. We review the most recent findings regarding the causes and consequences of HSC heterogeneity, discuss their far-reaching implications, and suggest that so-called continuum-based models may help consolidate apparently divergent experimental observations in this field.

Resolving cell cycle speed in one snapshot with a live-cell fluorescent reporter

“…We note that the median cell cycle length of the LKS compartment is determined by the division rate of the predominant population, which are the more proliferative multipotent progenitors (Passegue et al, 2005). The stem cell-enriched LKS compartment is known to be internally heterogeneous (Copley et al, 2012;Haas et al, 2018;McKenzie et al, 2006). This heterogeneity fluctuates diurnally (Méndez-Ferrer et al, 2009); remodels in response to injury (Haas et al, 2018); and evolves with aging (Beerman et al, 2010;Kowalczyk et al, 2015).…”

OMIP‐059: Identification of Mouse Hematopoietic Stem and Progenitor Cells with Simultaneous Detection of CD45.1/2 and Controllable Green Fluorescent Protein Expression by a Single Staining Panel

“…The number of surface markers is constantly increasing, leading to a steadily more detailed description and discrimination of the different cell populations. In parallel, functional and single cell data suggest a wide spectrum of molecular and functional heterogeneity (4,5). During the last years in particular HSCs and immediate downstream progenitors achieved high attention, as the hematopoietic system also serves as a model for other hierarchically organized stem cell systems.…”

Multifaceted roles of thrombopoietin in hematopoietic stem cell regulation

“…The difficulty of HSC purification may be due to the fact that HSCs are heterogeneous in surface marker expression and function. 33 While Thpo-Mpl pathway is implicated in the regulation of HSCs, the effect of the pathway on the expression of specific HSC-related genes seems to vary, suggesting that a specific subset of HSCs may respond to Thpo. HSCs from Thpo −/mice exhibited a significant decline in the expression of the Hoxb4, Hoxa5, Hoxa9, and Hoxa10 genes, but only small changes in Bmi1, Hif1a, Atm, and Tal1, which are all genes crucial for HSC self-renewal.…”

“…Along with the identification of heterogeneity in stem cell potential, recent studies have highlighted the heterogeneity in lineage differentiation, especially the megakaryocyte/platelet lineage, of HSCs. 33 Similar to Vwf + HSCs, HSCs expressing high levels of c-Kit differentiated with a bias to the megakaryocyte lineage. 35 The physiological relevance of HSCs preferentially differentiating to megakaryocytes lies possibly with the necessity for rapid action to stimulate platelet production under acute hematopoietic stress conditions that are likely complicated by life-threatening thrombocytopenia.…”