Reconstitution of thrombopoiesis by angiogenic factors

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DESCRIPTION (provided by applicant): Lineage-specific cytokines, including thrombopoietin (TPO), fail to reconstitute early phases of myelosuppression induced by irradiation, leading to prolonged life-threatening thrombocytopenia and bleeding complications. The long-term objective of this proposal is to demonstrate that pro- angiogenic factors with chemotactic activity, including Stromal Derived Factor-1 (SDF-1), SDF-1 analogue (CTCE-0214, Chemokine Therapeutics), FGF-4 and FGF-20 (CG53135, CuraGen), Kit-ligand (Amgen), VEGF-A and angiopoietin-1 by rapid regeneration of the bone marrow's (BM) vascular niche and recruitment of stem and progenitor cells could restore thrombopoiesis and facilitate engraftment of transplanted BM, after high dose radiation exposure. Within the BM, hematopoietic stem and progenitor cells reside in defined "niches", where they receive molecular and cellular instructions for proliferation, and differentiation. We have shown that recruitment of the megakaryocytic progenitors to the BM's vascular niche, supports their differentiation into functional platelets. Irradiation exposure to the BM not only induces rapid apoptosis of hematopoietic stem cells, but also damages the BM's vascular microenvironment. This leads to long-lasting life-threatening thrombocytopenia and engraftment failure after BM transplantation. Based on these studies, we hypothesize that angiogenic factors with stem and progenitor chemokine activity, such as SDF-1, FGF-4 and their analogues by rapid reconstitution of the vascular niche accelerates thrombopoiesis thereby protecting against life-threatening radiation-induced thrombocytopenia. In addition, angiogenic factors, including VEGF-A, Kit-ligand and angiopoietin-1 by enhancing the regeneration and stabilization of the vascular niche not only contribute to rapid restoration of thrombopoiesis, but also support engraftment of transplanted stem cells thereby augmenting restoration of thrombopoiesis after irradiation. These goals will be achieved through executing the following pre-clinical mechanistic studies: 1) Assess the potential of pro-angiogenic chemokines in accelerating thrombopoiesis after radiation-induced myelosuppression: 2) Determine the role of the angiogenic factors, VEGF-A, soluble Kit-ligand and angiopoietin-1, in regeneration of the BM's vascular niche to restore platelet recovery after irradiation 3) Evaluate the effectiveness of pre-conditioning of the BM microenvironment with FGFs, VEGF-A and Kit-ligand to accelerate regeneration of the vascular niche to enhance engraftment of stem cells after BM transplantation into the irradiated BM. We anticipate that clinical availability of the SDF-1 analogue, CTCE-0214 (Chemokine Therapeutics), FGF-20 (CuraGen, CG53135), Kit-ligand and upcoming clinical grade pro-angiogenic factors that are currently being evaluated in phase I clinical trials, would provide the platform for assessing the role of these agents in amelioration and rapid restoration of thrombocytopenia induced by irradiation as it might occur as a consequence of a nuclear fall out. Exposure to irradiation results in major damage to the bone marrow resulting in failure in blood production. This leads to development of major life-threatening bleeding and infection. Currently, the factors that could promote blood production, specifically platelets, are not effective in restoring bone marrow's function. We have discovered specific "angiogenic" factors that by activating the formation of the blood vessels in the bone marrow will also induce rapid generation of platelets thereby ameliorating fatal bleeding complications associated with high doses of radiation exposure. Furthermore, these angiogenic factors by facilitating rapid assembly of the blood vessels provide for a fertile ground for the engraftment of transplanted stem cells into the bone marrow's microenvironment. This will result in enhanced restoration of blood production and platelet recovery. Collectively, we predict that our studies will determine the optimal means to deliver these angiogenic factors to restore blood production, platelet recovery and augment stem cell engraftment thereby diminishing complications associated with a nuclear fall out.