Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells

Throughout life, one's blood supply depends on sustained division of hematopoietic stem cells (HSCs) for self-renewal and differentiation. Within the bone marrow microenvironment, an adhesiondependent or -independent niche system regulates HSC function. Here we show that a novel adhesion-dependent mechanism via integrin-beta 3 signaling contributes to HSC maintenance. Specific ligation of beta 3-integrin on HSCs using an antibody or extracellular matrix protein prevented loss of long-term repopulating (LTR) activity during ex vivo culture. The actions required activation of alpha v beta 3-integrin inside-out signaling, which is dependent on thrombopoietin (TPO), an essential cytokine for activation of dormant HSCs. Subsequent outside-in signaling via phosphorylation of Tyr747 in the beta 3-subunit cytoplasmic domain was indispensable for TPO-dependent, but not stem cell factor-dependent, LTR activity in HSCs in vivo. This was accompanied with enhanced expression of Vps72, Mll1, and Runx1, 3 factors known to be critical for maintaining HSC activity. Thus, our findings demonstrate a mechanistic link between beta 3-integrin and TPO in HSCs, which may contribute to maintenance of LTR activity in vivo as well as during ex vivo culture. (Blood. 2012; 119(1): 83-94)