Abstract
SummaryWe earlier showed that outside-in integrin signaling through POSTN-ITGAV interaction plays an important role in regulating adult hematopoietic stem cell (HSC) quiescence. Here, we show that Itgav deletion results in increased frequency of phenotypic HSCs in fetal liver (FL) due to faster proliferation. Systemic deletion of Postn led to increased proliferation of FL HSCs, albeit without any loss of stemness, unlike Vav-Itgav−/− HSCs. Based on RNA sequencing analysis of FL and bone marrow HSCs, we predicted the involvement of DNA damage response pathways in this dichotomy. Indeed, proliferative HSCs from Postn-deficient FL tissues showed increased levels of DNA repair, resulting in lesser double-strand breaks. Thus POSTN, with its expression majorly localized in the vascular endothelium of FL tissue, acts as a regulator of stem cell pool size during development. Overall, we demonstrate that the duality of response to proliferation in HSCs is developmental stage dependent and can be correlated with DNA damage responses.
Highlights
Emergence and maturation of hematopoietic stem cells (HSCs) takes place during embryonic development where fetal liver (FL) plays a central role (Muller et al, 1994)
Expression of av and b3 Integrin Chains in FL-Derived Primitive HSCs We first examined the expression of ITGAV and its binding partner ITGB3 in embryonic day 14.5 (E14.5) FL HSCs
The expression of Itgav and Itgb3 was observed to be low in HSCs from all embryonic stages (Figure 1C, S1A, and S1B), consistent with our earlier published results that established POSTN-ITGAV interaction as a negative regulator of bone marrow (BM)-HSC proliferation
Summary
Emergence and maturation of hematopoietic stem cells (HSCs) takes place during embryonic development where fetal liver (FL) plays a central role (Muller et al, 1994). Little is known about fetal HSC niches, but recent evidence from Paul Frenette’s group has shown the importance of cells associated with portal vessels in supporting HSCs in the FL tissue (Khan et al, 2016). Significant genetic differences were observed in the cells that supported proliferative HSCs in FL tissue and the niche cells of the adult BM-derived HSCs (Khan et al, 2016). These differences notwithstanding, it has been sufficiently well established that association with their niches is crucial to the optimal functioning of fetal as well as adult HSCs (Gao et al, 2018)
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