Deletion of Fak in Hematopoietic Stem Cells Leads to Enhanced Engraftment

Hematopoietic stem and progenitor cells (HSPC) can be induced to leave the bone marrow (BM) and such mobilized hematopoietic stem cell (HSC) enriched cell populations when infused intravenously rapidly home back to the marrow and transmigrate into the extravascular compartment where they lodge in specialized niches. Niche induced signals coupled to intrinsic factors, promote HSC maintenance and regulate HSC localization, migration and/or differentiation. A better understanding of molecular pathways governing these HSC fate decisions could identify new targets for ex vivo HSC expansion and improvement of transplantation. Focal adhesion kinase (Fak) is a non-receptor protein tyrosine kinase, whose function has been well studied in fibroblasts, where it plays an important role in cell adhesion, survival and motility. Fak is also differentially expressed in HSPC, with highest expression in long-term HSCs (LT-HSCs, Lin-Sca-1+c-Kit +CD34-). Its functional role in hematopoiesis has not been well studied due to early embryonic lethality (E.8) of Fak−/− mice. We have generated conditional Fak deleted mice (Fakfl/flMx1-Cre+) to define how Fak signaling contributes to different components of HSC transplantation. We observed that the total cellularity in BM was comparable between Fak knockout (Fak−/−Mx1-Cre+) and control (Fakfl/fl) mice. The frequencies of both Lin-Sca-1+c-Kit + cells (LSKs) and short-term HSCs (ST-HSCs, Lin-Sca-1+c-Kit +CD34+) increased 2-fold in BM of Fak knockout mice compared to WT controls (n=5; p