The enforced proliferation of hematopoietic stem cells (HSCs) replicates features of their aging. In Cell, Bernitz et al. investigate how proliferative history correlates with lineage-reconstitution potential. The authors use a H2B-GFP label-retaining system in which all the long-term (LT) hematopoietic activity is contained in a population of rarely dividing GFPhi HSCs. Through the use of GFP dilution to quantify cell division in vivo and mathematical modeling of the effect of division history on the progression of HSCs through the cell cycle, the authors define a model in which HSCs undergo four symmetric self-renewal divisions, followed by a state of dormancy. Once they have lost the GFP label due to cell division, HSCs acquire the expression of CD41, a marker that in HSCs correlates with diminished quiescence, higher cycling rates and myeloid bias. According to this model, the fifth division results in the loss of LT-HSC potential and generates HSCs with limited self-renewal ability and a myeloid-differentiation bias. LT-HSCs are thought to divide five times during the lifespan of a mouse.

Cell 167, 1296–1309 (2016)