Single-cell fate decisions of bipotential hematopoietic progenitors

Abstract

Purpose of review: In hematopoiesis, rapid cell fate decisions are necessary for timely responses to environmental stimuli resulting in the production of diverse types of blood cells. Early studies have led to a hierarchical, tree-like view of hematopoiesis with hematopoietic stem cells residing at the apex and serially branching out to give rise to bipotential progenitors with increasingly restricted lineage potential. Recent single-cell studies have challenged some aspects of the classical model of hematopoiesis. Here, we review the latest articles on cell fate decision in hematopoietic progenitors, highlighting single-cell studies that have questioned previously established concepts and those that have reaffirmed them.

Recent findings: The hierarchical organization of hematopoiesis and the importance of transcription factors have been largely validated at the single-cell level. In contrast, single-cell studies have shown that lineage commitment is progressive rather than switch-like as originally proposed. Furthermore, the reconstruction of cell fate paths suggested the existence of a gradient of hematopoietic progenitors that are in a continuum of changing fate probabilities rather than in a static bipotential state, leading us to reconsider the notion of bipotential progenitors.

Summary: Single-cell transcriptomic and proteomic studies have transformed our view of lineage commitment and offer a drastically different perspective on hematopoiesis.

Figure 1.. Model of hematopoiesis based on a continuum of changing fate probabilities

(a) A putative hematopoietic progenitor with specific cell fate potential for various lineages is shown in the middle. Depending on cell culture conditions (top) or in vivo environments (bottom) this same cell can reveal different fates. This illustrates the uncertainty of inferring cell potential from cell fate measurements, both in vitro and in vivo. (b) In this model, hematopoiesis entails gradual changes in cell fate probabilities as progenitors progress along lineage trajectories. The extracellular environment (the niche) can alter cell fate probabilities in all progenitors but its influence gradually decreases during differentiation. In this model there are no bipotential progenitors per se, only progenitors with variable levels of restriction.

Figure 2.. Proposed mechanism for regulation of cell fate potential at the molecular level.

Cell potential in hematopoietic stem/progenitor cells is defined by a combination of several factors: 1) TFs that establish gene transcription programs and introduce epigenetic marks on chromatin; 2) chromatin structure that influences TFs by preventing or promoting their binding to specific genomic locations; 3) External signals from the environment that influence TFs and chromatin structure to allow fate plasticity.