Differentiation-based model of hematopoietic stem cell functions and lineage pathways

Advances in genetic labeling and barcoding of hematopoietic stem cells (HSCs) in situ now allow direct measurements of physiological HSC output, both quantitatively and qualitatively. Turning on a heritable label in HSCs and measuring the kinetics of label emergence in downstream compartments reveal rates of differentiation and self-renewal of HSCs and progenitor cells, whereas endogenous HSC barcoding probes physiological precursorproduct relationships. Labels have been inserted at different stages of the hematopoietic differentiation hierarchy. Recent genetic and functional evidence suggests a phenotype (Tie21) for tip HSCs. Fate mapping shows that many tip HSCs regularly feed into downstream stages, with individual cells contributing infrequently. Stem and progenitor cells downstream of tip HSCs serve as a major, nearly self-renewing source of day-to-day hematopoiesis, rendering the blood and immune system HSC-independent for extended periods of time. HSCs realizemultilineage output, yet, fates restricted to several lineages or even a single lineage have also been observed. Single HSCs within a clone in the bonemarrow that develop from a fetal HSC precursor have been observed to express clone-specific fates. Thus, the new tools probing HSC differentiation in situ are progressing beyond assays for HSC activity based on proliferation measurements and fates of transplanted stem cells, and the data challenge lineage interpretations of single-cell gene expression snapshots. Linking in vivo fate analyses to gene expression and othermolecular determinants of cell fate will aidin unraveling themechanisms of lineage commitment and the architecture of physiological hematopoiesis.