Niche-induced signaiing in HSCP transplantation. Children's Hospital Project Leader: Leslie E. Silberstein, M.D. Professor of Pathology, Harvard Medical School Director, Joint Program in Transfusion Medicine Children's Hospital Boston, Brigham and Women's Hospital, Dana-Farber Cancer Institute Director, Center for Human Cell Therapy, Immune Disease Institute Hematopoietic stem and progenitor cells (HSCP) can be induced to leave the BM, e.g. mobilization, 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. 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. Our own studies and those of others, suggest that also in hematopoietic cells Fak functions as a key integrator of external/BM niche signals such as adhesion molecules, stem cell factor and CXCL12. Due to early embryonic lethality (E.S) of Fak'^'mice, homozygous Fak fl/fl mice were bred to the IFN-inducible Mxl-Cre transgene that elicits widespread efficient gene deletion throughout the hematopoietic system, including HSCs. Conditional Fak deletion in the hematopoietic compartment results in an expanded HSC population with a two-fold, long-term enhanced engraftment of at least 20 weeks duration, e.g. Mxl-Cre Fak deleted phenotype. We hypothesize that the Mxl-Cre Fak deleted phenotype results from perturbations of the interactions between HSCs and the BM microenvironment. However, it is unclear how Fak signaling affects HSC homeostasis/engraftment and thus three aims are proposed to explore the following, non-mutually exclusive possible mechanisms.
Aim 1 will determine if FAK regulates HSC number and function;
Aim 2 will assess the relative contribution of Fak inactivation in HSC and niche cells to the hematopoietic phenotype of Mxl-Cre Fak fl/fl mice (Mx^-Cre Fak deleted phenotype);
and Aim 3 will determine if Fak regulates HSC distribution and/or lodgement in bone marrow. A better understanding ofthe molecular pathways controlling HSC homeostasis should lead to new translational approaches to enhance ex vivo expansion and improve transplantation efficiency of clinically relevant HSCP populations. Such strategies are especially needed in settings where the quantity and/or quality of HSCs affect transplant efficiency, i.e. HSCs from placental/umbilical cord blood or HSCs from individuals in whom it is difficult to isolate adequate numbers of HSCs for therapy. Improvement in the time to engraftment would limit the morbidity of transplant recipients and diminish the need for blood products to manage cytopenias in the immediate post-transplant period.
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