Unperturbed vs. post-transplantation hematopoiesis: both in vivo but different

Abstract

Purpose of review: Hematopoietic stem cell (HSC) transplantation has yielded tremendous information on experimental properties of HSCs. Yet, it remains unclear whether transplantation reflects the physiology of hematopoiesis. A limitation is the difficulty in accessing HSC functions without isolation, in-vitro manipulation and readout for potential. New genetic fate mapping and clonal marking techniques now shed light on hematopoiesis under physiological conditions.

Recent findings: Transposon-based genetic marks were introduced across the entire hematopoietic system to follow the clonal dynamics of these tags over time. A polyclonal source downstream from stem cells was found responsible for the production of at least granulocytes. In independent experiments, HSCs were genetically marked in adult mice, and the kinetics of label emergence throughout the system was followed over time. These experiments uncovered that during physiological steady-state hematopoiesis large numbers of HSCs yield differentiated progeny. Individual HSCs were active only rarely, indicating their very slow periodicity of differentiation rather than quiescence.

Summary: Noninvasive genetic experiments in mice have identified a major role of stem and progenitor cells downstream from HSCs as drivers of adult hematopoiesis, and revealed that post-transplantation hematopoiesis differs quantitatively from normal steady-state hematopoiesis.

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FIGURE 1

Schematic depiction of HSC diversity and contribution to hematopoiesis tested in transplantation or by fate mapping. (a) Transfer of HSC leads to a transient multiclonal contribution in the first weeks after injection. The majority of HSC clones is lost within the first 4 months, and long-term engraftment is achieved by only a few dominating HSC clones. Individual clones are symbolized by colored lines. (b) Tamoxifen induces Cre/loxP-mediated recombination of the Rosa26 reporter locus, resulting in YFP-expression in Tie2+ HSCs and their progeny. This reveals polyclonal participation of many HSCs in hematopoiesis, with each individual HSC contributing only rarely (on average about once every 110 days, with perhaps some variation in individual timing) [^▪▪]. Individual clones are indicated by colored lines, and waves indicate periods of activity. HSC, hematopoietic stem cell; Mer, mutated estrogen receptor site; MerCreMer, Cre recombinase fused to two Mer sites.