The role of stromal cell-derived factor-1 in cell mobilization, cell homing and neovascularization following stroke

Abstract

Stroke is the 3rd leading cause of death and the leading cause of long-term disability in the U.S. With only one approved drug presently used in clinics, there is a great need for the development for new therapeutic targets. Stromal cell derived factor-1 (SDF-1) is a small chemokine that may aid in cerebral repair following stroke. Acting primarily through the CXCR4 receptor, SDF-1 is known to be chemotactic for neuroblasts, endothelial cells, and bone marrow derived (BMD) cells including stem and progenitor cells found in the bone marrow. Recently, BMD stem/progenitor cells have become widely studied for their potential role in tissue repair following ischemia. SDF-1 is under hypoxic regulation and is highly expressed in ischemic brain tissue for at least 30 days following ischemia suggesting it may play role in long term repair or remodeling. The goal of these studies is to determine the role of SDF-1 in cerebral repair following stroke. I hypothesize that SDF-1 upregulaton during brain ischemia contributes to tissue repair and neurological recovery by inducing the homing of bone marrow-derived cells to the site of injury and neovascularization. In a mouse middle cerebral artery ligation (MCAL) permanent occlusion stroke model, I investigated mobilization, homing, and differentiation of adult bone marrow derived (BMD) cells in response to SDF-1 induced by cerebral ischemia. Results presented in this dissertation show that SDF-1 induces mobilization of BMD cells following stroke. Once mobilized, BMD cells homed to the brain and either retained their blood cell phenotypes (i.e. monocytes and neutrophils) or they differentiated mostly into microglia cells. Many BMD cells migrated to a perivascular location with a subset becoming pericytes. Additionally, I found that SDF-1 induced neovascularization and this occurs through a combination of angiogenic and vasculogenic processes in the in vivo stroke model as well as in an in vitro tube formation assay. However, we did not detect beneficial preservation of brain tissue or augmented functional recovery with treatment of SDF-1, but it remains to be determined if altering timing, delivery, or isoform-specificity of SDF-1 may be therapeutically beneficial.