Clonal dynamics of native haematopoiesis

Abstract

It is currently thought that life-long blood cell production is driven by the action of a small number of multipotent haematopoietic stem cells. Evidence supporting this view has been largely acquired through the use of functional assays involving transplantation. However, whether these mechanisms also govern native non-transplant haematopoiesis is entirely unclear. Here we have established a novel experimental model in mice where cells can be uniquely and genetically labelled in situ to address this question. Using this approach, we have performed longitudinal analyses of clonal dynamics in adult mice that reveal unprecedented features of native haematopoiesis. In contrast to what occurs following transplantation, steady-state blood production is maintained by the successive recruitment of thousands of clones, each with a minimal contribution to mature progeny. Our results demonstrate that a large number of long-lived progenitors, rather than classically defined haematopoietic stem cells, are the main drivers of steady-state haematopoiesis during most of adulthood. Our results also have implications for understanding the cellular origin of haematopoietic disease.

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

“…Overall, our data are consistent with behavioral features of individual HSC clones being established in development prior to young adulthood and persistently manifest under varying conditions. Lineage bias and proliferative potency has been demonstrated previously (Dykstra et al, 2007;Morita et al, 2010;Muller-Sieburg et al, 2004;Picelli et al, 2013), including at the clonal level (Sun et al, 2014b). The data here indicate that multiple other characteristics including sensitivity to inflammation or radiation are also clone-specific features.…”

“…These include cells that have distinctive behaviors in terms of cell production and lineage bias (Dykstra et al, 2007;Picelli et al, 2013). Hematopoietic stem cells have been demonstrated to exhibit bias toward myeloid, lymphoid, or megakaryocytic lineage upon transplantation of single cells (Dykstra et al, 2007(Dykstra et al, , 2011Morita et al, 2010), on ex vivo barcoding and transplantation of populations (Aiuti et al, 2013;Gerrits et al, 2010;Jordan and Lemischka, 1990;Lemischka, 1993;Lemischka et al, 1986;Lu et al, 2011;Mazurier et al, 2004;Shi et al, 2002;Snodgrass and Keller, 1987), or by retrotransposon tagging of endogenous cells (Sun et al, 2014b). Further, single-cell transplant data have been coupled with single-cell gene expression analysis on different cells to resolve subpopulations with corresponding gene expression and repopulation potential (Wilson et al, 2015).…”

Mechanisms of self-renewal in hematopoietic stem cells

“…These cells usually express high levels of CXCL12 and stem cell factor (SCF). By inserting green fluorescent protein (GFP) into the endogenous Scf locus, Clonal behaviors of HPCs and HSCs are illustrated based on our interpretation of published data [1]. a Most HPCs are in the G0 state but differentiate into mature blood after varied periods of time.…”

“…It has been long thought that HSCs are required for the development, maintenance, and regeneration of the hematopoietic system. A completely new view of hematopoiesis was provided recently by Camargo and his colleagues [1]. A new marking method using Sleeping Beauty transposase permitted long-term interest in stem cell biology is to understand how self-renewal is regulated in HSCs.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…An extensive body of literature exists on how hematopoiesis occurs, the various molecules regulating this process, and how this process can be perturbed in disease (1)(2)(3). While many questions remain to be addressed, such as the exact hierarchical arrangement of cells that produce the blood (4,5), much more is understood about this system compared with most other aspects of cell differentiation observed in physiology. Yet despite our sophisticated understanding of hematopoiesis, the ability to explain a number of clinical observations in patients with blood disorders is often limited.…”