Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking

Kruppel-like factor 5 regulates pluripotent stem cell self-renewal, but its role in somatic stem cells is unknown. Here we show that Kruppel-like factor 5-deficient haematopoietic stem cells and progenitors fail to engraft after transplantation. This haematopoietic stem cell and progenitor defect is associated with impaired bone marrow homing and lodging and decreased retention in bone marrow, and with decreased adhesion to fibronectin and expression of membrane-bound beta 1/beta 2-integrins. In vivo-inducible gain-of-function of Kruppel-like factor 5 in haematopoietic stem cells increases haematopoietic stem cell and progenitor adhesion. The expression of Rab5 family members, mediators of beta 1/beta 2-integrin recycling in the early endosome, is decreased in Klf5(Delta/Delta) haematopoietic stem cells and progenitors. Kruppel-like factor 5 binds directly to the promoter of Rab5a/b, and overexpression of Rab5b rescues the expression of activated beta 1/beta 2-integrins, adhesion and bone marrow homing of Klf5(Delta/Delta) haematopoietic stem cells and progenitors. Altogether, these data indicate that Kruppel-like factor 5 is indispensable for adhesion, homing, lodging and retention of haematopoietic stem cells and progenitors in the bone marrow through Rab5-dependent post-translational regulation of beta 1/beta 2 integrins.