| First Author | Umemoto T | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 1 | Pages | 83-94 |
| PubMed ID | 22096247 | Mgi Jnum | J:181799 |
| Mgi Id | MGI:5314191 | Doi | 10.1182/blood-2011-02-335430 |
| Citation | Umemoto T, et al. (2012) Integrin-alphavbeta3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells. Blood 119(1):83-94 |
| abstractText | 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 adhesion-dependent or -independent niche system regulates HSC function. Here we show that a novel adhesion-dependent mechanism via integrin-beta3 signaling contributes to HSC maintenance. Specific ligation of beta3-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 alphavbeta3-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 beta3-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 beta3-integrin and TPO in HSCs, which may contribute to maintenance of LTR activity in vivo as well as during ex vivo culture. |
