Pleiotrophin Improves Survival Following Radiation-Induced Myelosuppression and Mediates HSC Expansion Via Induction Of Ras Signaling

Discovery of the mechanisms through which the bone marrow microenvironment stimulates hematopoietic regeneration following myelosuppression could lead to therapies to accelerate hematopoietic reconstitution in patients receiving chemotherapy, total body irradiation and stem cell transplantation. We have previously shown that treatment with pleiotrophin (PTN), a heparin-binding growth factor which is secreted by BM endothelial cells (ECs), causes a 10-fold expansion of murine long term-HSCs in culture (Himburg et al. Nat Med 2010). More recently, we demonstrated that PTN-deficient mice have a >10-fold deficit in LT-HSCs and hematopoietic regenerative capacity compared to PTN+/+ mice, suggesting an important role for PTN in maintaining the HSC pool in vivo (Himburg et al. Cell Reports 2012). In keeping with this, 100% of PTN-deficient mice died prior to day +30 following 700 cGy total body irradiation (TBI) compared to 30% mortality in irradiated, PTN+/+ mice (P Disclosures: No relevant conflicts of interest to declare.