Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice

Tatyana Grinenko,Anja Krüger,Ingmar Glauche,Onur Basak,Alexander Gerbaulet,Lars Thielecke,Anne Eugster,Triantafyllos Chavakis,Malte Von Bonin,Sevina Dietz,Beáta Ramasz,Ben Wielockx,Hans Clevers

doi:10.1038/s41467-018-04188-7

Abstract

Hematopoietic stem cells (HSCs) continuously replenish all blood cell types through a series of differentiation steps and repeated cell divisions that involve the generation of lineage-committed progenitors. However, whether cell division in HSCs precedes differentiation is unclear. To this end, we used an HSC cell-tracing approach and Ki67RFP knock-in mice, in a non-conditioned transplantation model, to assess divisional history, cell cycle progression, and differentiation of adult HSCs. Our results reveal that HSCs are able to differentiate into restricted progenitors, especially common myeloid, megakaryocyte-erythroid and pre-megakaryocyte progenitors, without undergoing cell division and even before entering the S phase of the cell cycle. Additionally, the phenotype of the undivided but differentiated progenitors correlated with the expression of lineage-specific genes and loss of multipotency. Thus HSC fate decisions can be uncoupled from physical cell division. These results facilitate a better understanding of the mechanisms that control fate decisions in hematopoietic cells.

Highlights

Hematopoietic stem cells (HSCs) continuously replenish all blood cell types through a series of differentiation steps and repeated cell divisions that involve the generation of lineage-committed progenitors
Shimoto et al have shown that numerous empty HSC niches are available upon transplantation into nonconditioned recipients, which are located distant from filled niches and available for HSC engraftment and proliferation
Based on surface staining at 36 h posttransplantation, we subdivided donor myeloid progenitors (MPs) into the following restricted progenitors: common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs) (Lin− Sca1− Kit+ CD41− CD150− CD16/32+), PreMEs, and PreMegs (Fig. 1b)

Summary

Introduction

Hematopoietic stem cells (HSCs) continuously replenish all blood cell types through a series of differentiation steps and repeated cell divisions that involve the generation of lineage-committed progenitors. Most adult HSCs normally exist in a quiescent or dormant state[2], some of them divide and support the production of all mature blood cell types through multiple intermediate progenitor stages, during steady state, and in response to acute needs[3,4,5] These include myeloid progenitors (MPs), encompassing restricted progenitors like common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), pre-megakaryocyte-erythroid progenitors (PreMEs), and pre-megakaryocyte progenitors (PreMegs). HSC transition through the multipotent and restricted progenitor stages is accompanied by intense cell proliferation[3] It is unclear whether each fate decision step is associated with one or more division events or whether cell proliferation and differentiation are independent processes. Our data demonstrate that the G0/G1 phases are important for fate decision in HSCs to either differentiate or self-renew

Methods

Results

Conclusion