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

Hdl Handle:
http://hdl.handle.net/10675.2/318798
Title:
The role of stromal cell-derived factor-1 in cell mobilization, cell homing and neovascularization following stroke
Authors:
Walker, Aisha L.
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.
Affiliation:
Department of Cellular Biology and Anatomy
Issue Date:
Nov-2007
URI:
http://hdl.handle.net/10675.2/318798
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304403934?accountid=12365
Type:
Dissertation
Language:
en_US
Appears in Collections:
Theses and Dissertations; Department of Cellular Biology and Anatomy Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorWalker, Aisha L.en
dc.date.accessioned2014-06-03T18:12:38Z-
dc.date.available2014-06-03T18:12:38Z-
dc.date.issued2007-11-
dc.identifier.urihttp://hdl.handle.net/10675.2/318798-
dc.description.abstractStroke 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.en
dc.language.isoen_USen
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304403934?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.-
dc.subjectStromal Cell-Derived Factor-1en
dc.subjectSDF-1en
dc.subjectCXCL12en
dc.subjectStrokeen
dc.subjectIschemiaen
dc.subjectMiddle Cerebral Artery Ligationen
dc.subjectNeovascularizationen
dc.subjectBone Marrow-Derived cellsen
dc.subjectMesenchymal Stem Cellsen
dc.subjectEndothelial Cellsen
dc.subjectCXCR4en
dc.subjectChemokineen
dc.subjectCell Homingen
dc.subjectMobilizationen
dc.subjectMouseen
dc.titleThe role of stromal cell-derived factor-1 in cell mobilization, cell homing and neovascularization following strokeen
dc.typeDissertationen
dc.contributor.departmentDepartment of Cellular Biology and Anatomyen
dc.description.advisorHill, William D.-
dc.description.committeeNot Listed-
dc.description.degreeDoctor of Philosophy (Ph.D.)-
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