PROLIFERATION, DNA DAMAGE RESPONSE AND HEMATOPOIETIC STEM CELL FUNCTION: A DYNAMIC, CONTEXT DEPENDENT RELATION

Proliferation in hematopoietic stem cells (HSCs) has been linked to stemness. A variety of mouse transgenic lines with increased HSC proliferation rates have shown concomitant deterioration of their function (Dev. Dyn. 2016). While some studies implicated DNA damage accumulation as the underlying reason (Walter D. et al. in Nature 2015), others have maintained that, in fact, quiescence of primitive HSCs might be the reason behind poor resolution of DNA damages (Mohrin M et al. in Cell Stem Cell 2010). In our earlier studies, we demonstrated that outside-in integrin signaling is important to maintain HSC quiescence (Khurana S. et al. in Nat. Comm. 2016). We showed loss of HSC function in mice deficient in interaction between Integrin-αv (Itgav; Vav-Itgav-/- mice) and its ligand Periostin (Postn; Postn-/- mice). Our recent studies show that increase in proliferation of fetal liver (FL) HSCs in these mice results in their efficient expansion without any loss of function. Postn deficient FL tissues showed clear increase in the frequency of primitive HSCs with long-term engraftment potential. They proliferated faster, without any functional decline. However, Vav-Itgav-/- FL HSCs transiting from proliferative to quiescent phenotype showed dependence on Itgav-Postn interaction for quiescence and functional integrity. On the basis of RNASeq based differential pathway analysis using BM and E14.5 FL derived HSCs, we hypothesized that better DNA damage response (DDR) pathways in FL derived HSCs could result in these observations. In deed we observed that HSCs derived from FL show better resistance to DNA damage than adult bone marrow. We went on to show the importance of integrin ligand Postn in the creation of hematopoietic niche in FL tissue. Overall, we propose through our results that proliferation in HSCs affects HSC function in developmental context dependent manner.