3077 - Developmental Stage Dependent Response to Proliferation in Hematopoietic Stem Cells

Abstract

Earlier we showed that Periostin (Postn) through interaction with integrin-v plays important role in maintenance of adult hematopoietic stem cell (HSC) quiescence (Khurana S. et al. in Nat. Comm. 2016). We here show that interruption in this interaction leads to increased proliferation of HSCs in fetal liver (FL) without any loss of stemness, expanding the stem cell pool. At E14.5, Postn-/- fetuses showed increased frequency of primitive FL HSCs, which proliferated faster without losing their in vivo repopulation capacity. There was a similar increase in the frequency of HSCs in Vav-Itgav-/- fetuses. However, following transplantation, as they transitioned from fetal to adult phenotype, the Itgav-/- FL HSCs showed dependence on interaction with Postn. We tried to uncover the cause of this duality of response to proliferation in fetal versus adult HSCs. Intrinsic gene expression studies revealed metabolic differences between FL and adult BM HSCs (Manesia JK in Stem Cell Res. 2015). In addition, we observed significant differences between DNA damage responses in fetal versus adult HSCs. BM derived HSCs as compared with their FL counterparts accumulated more DNA damage when stimulated to proliferate. Gene expression studies, comet assays and -H2AX staining confirmed differential DNA damage response pathways in FL versus BM HSCs. Overall, we present the data showing that stemness of HSCs is affected by proliferation in a developmental stage dependent manner and DDR pathways could play important role in it.