Clonal Analysis Unveils Self-Renewing Lineage-Restricted Progenitors Generated Directly from Hematopoietic Stem Cells

Abstract

Consensus holds that hematopoietic stem cells (HSCs) give rise to multipotent progenitors (MPPs) of reduced self-renewal potential and that MPPs eventually produce lineage-committed progenitor cells in a stepwise manner. Using a single-cell transplantation system and marker mice, we unexpectedly found myeloid-restricted progenitors with long-term repopulating activity (MyRPs), which are lineage-committed to megakaryocytes, megakaryocyte-erythroid cells, or common myeloid cells (MkRPs, MERPs, or CMRPs, respectively) in the phenotypically defined HSC compartment together with HSCs. Paired daughter cell assays combined with transplantation revealed that HSCs can give rise to HSCs via symmetric division or directly differentiate into MyRPs via asymmetric division (yielding HSC-MkRP or HSC-CMRP pairs). These myeloid bypass pathways could be essential for fast responses to ablation stress. Our results show that loss of self-renewal and stepwise progression through specific differentiation stages are not essential for lineage commitment of HSCs and suggest a revised model of hematopoietic differentiation.

Identification of DNA methylation changes atcis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing

“…Flow cytometry-based protocols allow the prospective isolation of bone marrow HSCs and MPPs based upon correlations between immunophenotype and functional characteristics following transplantation. [1][2][3][4] MPPs are capable of differentiating into all mature haematopoietic lineages but, in contrast to quiescent HSCs, harbor only restricted self-renewal capacity as reflected by their transient reconstitution capacity following transplantation. Sub-fractions of the MPP compartment demonstrate differences in proliferative status under homeostatic conditions and also show divergent functional behavior upon transplantation.…”

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

“…Fascinatingly, these properties appear to be largely intrinsically stable within the original HSC and its progeny (reviewed in [2]), although external stimuli (usually described under the blanket term of "niche") can influence HSC behaviour (reviewed in [3]). This heterogeneity of HSC has been brought to light specifically in terms of MK differentiation by the demonstration by two independent groups of a previously undescribed subpopulation of HSCs which is "primed" to preferentially differentiate to the MK lineage [4,5]. This suggests HSCs do not necessarily need to go through the multipotent progenitor stage.…”

Maintenance of hematopoietic stem cell dormancy: yet another role for the macrophage

“…Instead it appears as though ST-HSC as well as more differentiated progenitors with selfrenewing abilities are the predominant suppliers of new blood cells (11,22), implying that LT-HSC primarily serve as a reservoir in the adult hematopoietic system. In addition, current data suggest that commitment to a specific lineage during the hematopoietic differentiation process, starting with ST-HSC, primarily reflects cell-autonomous features of the relevant cell type (23)(24)(25)(26). The primary role of the LT-HSC niche may thus be to enforce quiescence in order to protect the stem cell pool from proliferative exhaustion and accumulation of DNA damage.…”