Fundamental properties of unperturbed haematopoiesis from stem cells in vivo

Abstract

Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ∼5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.

Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells

“…The results indicate that endogenous hematopoiesis is a composite of highly heterogeneous clones with very different cell kinetics, roughly balancing multipotent clones that are transient (generating cells for short intervals) with clones that provide persistent cell output. These data are consistent with the recent findings of Busch et al (2015) where pulsed labeling of the pool of HSC was used to model cell kinetics. HSC were found to infrequently (~1/110 HSC per day) generate downstream progeny producing blood cells while maintaining the HSC pool.…”

FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential

“…In vitro, many tissue SCs, including epidermal and HFSCs, can be passaged long-term without loss of their tissue-regenerating capability (19)(20)(21)(22)(23). In vivo, SC markers can lineage-trace progeny that survive in tissues long term (24,25), although a recent detailed study of hematopoietic SC (HSCs) self-renewal suggests that adult homeostasis may be sustained by multiple short-term SCs that receive rare input from polyclonal long-term HSC (26,27). In all of these cases, the outcome is long-term ability to regenerate the tissue.…”

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

“…HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress.…”