Novel Function of FGFR1 in Hematopoietic Stem Cell Stress Response.

The hematopoietic stem cell (HSC) is one of the best characterized tissue-specific stem cells in adult mammals, yet a great deal remains to be learned about the signaling pathways involved in its regulation. Fibroblast growth factors (FGFs), a large family of cytokines, and their cell-surface receptors (FGFRs) are known to play key roles in regulating cell proliferation, differentiation, and migration, both during embryonic development and in the adult. Although HSCs are known to express certain FGF pathway components, the functional significance of this is not well understood. In order to investigate the contribution of FGF signaling to HSC regulation, we generated a conditional Mx1-Cre/FGFR1fx/fx knockout mouse line. Though lacking an overt phenotype within the hematopoietic system under homeostatic conditions, these mice displayed defects in mobilization of HSCs to the peripheral circulation and spleen after myelosuppression with the chemotherapeutic agent 5-fluorouracil (5-FU), as compared to littermate controls. We are currently exploring the mechanism of this defect by directly testing the migratory ability of a population of bone marrow cells containing stem and progenitor cells. Of interest are cells from FGFR1 knockout mice that displayed defective migration toward recombinant chemokine (C-X-C motif) ligand 12 (CXCL12), indicating a link between FGF signaling and CXCL12/CXCR4-mediated chemotaxis, a process with known roles in mobilization. We competitively transplanted LSK/Flk2- cells (a population highly enriched for HSCs) from FGFR1 knockout and control mice into lethally irradiated recipients to test their repopulation ability. Our findings indicate an important role for signaling through FGFR1 in the mobilization of HSCs in mice, knowledge which may enhance clinical mobilization protocols.