Epidermal Growth Factor-like Domain 7 Promotes Hematopoietic Stem Cell Expansion and Increases Myeloid-Megakaryocytic Lineage Priming through beta3 Integrin

Interactions between stem cells and their surrounding microenvironment, or niche, are critical for the establishment and maintenance of stem-cell properties. Niche cells within the bone marrow (BM) are contacted by the hematopoietic stem cells (HSCs), which retain their stem-cell character through the direct association with these niche cells. Within the BM microenvironment, an adhesion-dependent or -independent niche system regulates HSC function. Here we show that the extracellular matrix protein epidermal growth factor-like domain protein 7 (Egfl7) induced HSCs to enter the cell cycle and to undergo myelo-megakaryocytic differentiation both under steady state conditions and after myelosuppression in vivo. Mechanistically, we show that Egfl7 binds to the beta₃ integrin expressed on HSCs, thereby activating the Akt pathway in HSCs. In beta₃^-/- mice, Egfl7-mediated HSC expansion, cell cycle progression and myelo-megakaryocytic differentiation did not occur. We propose that the ECM protein Egfl7 recruits dormant HSCs into active cell cycle, and can govern stress-induced hematopoiesis by beta₃ integrin-dependent anchoring to the stem cell niche.