CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells

Elisa Laurenti,Catherine Frelin,Stephanie Xie,Robin Ferrari,Cyrille F Dunant,Sasan Zandi,Andrea Neumann,Ian Plumb,Sergei Doulatov,Jing Chen,Craig April,Jian-Bing Fan,Norman Iscove,John E Dick

doi:10.1016/j.stem.2015.01.017

Abstract

SummaryRegulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unknown. We report here that quiescence exit kinetics are differentially regulated within human HSC subsets through the expression level of CDK6. LT-HSCs lack CDK6 protein. Short-term (ST)-HSCs are also quiescent but contain high CDK6 protein levels that permit rapid cell cycle entry upon mitogenic stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impacting function. Computational modeling suggests that this independent control of quiescence exit kinetics inherently limits LT-HSC divisions and preserves the HSC pool to ensure lifelong hematopoiesis. Thus, differential expression of CDK6 underlies heterogeneity in stem cell quiescence states that functionally regulates this highly regenerative system.

Highlights

Hematopoiesis ensures that blood demand is met under homeostatic and stress conditions through tightly controlled regulation of hematopoietic stem cells (HSCs) and their progeny
Heterogeneity in the Human HSC Pool The cycling properties of mouse HSC subpopulations are described, but they have not been validated in the human HSC hierarchy
Human LT-HSCs, isolated from umbilical cord blood (CB) as LinÀ CD34+ CD38À CD45RAÀ CD90+ CD49f+ (Notta et al, 2011), provide robust multilineage repopulation beyond 30 weeks in the NSG mouse xenograft assay with about 10% frequency (Notta et al, 2011) and efficiently engraft upon secondary transplantation (Table S1)

Summary

Introduction

Hematopoiesis ensures that blood demand is met under homeostatic and stress conditions through tightly controlled regulation of hematopoietic stem cells (HSCs) and their progeny. Functional self-renewal of HSCs is associated with reduced cell cycle activity. (3) The HSC pool has been fractionated into long-term (LT-), intermediate-term (IT-), short-term (ST-) HSCs and multipotent progenitors (MPPs) and is hierarchically organized based on progressively reduced repopulation capacity and increased cycling properties (Benveniste et al, 2010; Cheshier et al, 1999; Copley et al, 2012; Foudi et al, 2009; Oguro et al, 2013; Passegueet al., 2005; Qiu et al, 2014; Wilson et al, 2008). While the hierarchically organized HSC subsets are widely thought to prevent HSCs exhaustion and preserve lifelong blood production, knowledge of the molecular mechanisms that govern the variable cycling properties of each HSC subset is lacking

Results

Discussion

Conclusion