Cell based restoration of motor function in rodent models of Parkinson's disease and stroke

Abstract

Parkinson`s disease (PD) and Ischemic stroke are common disorders in our aging population. Although a large body of basic research highlights the potential of cell replacement therapy (CRT) as a novel therapeutic approach, clinical translation remains a distant goal. CRT has been most successfully applied in the (PD) field where clinical trials with human foetal tissue have established proof-of principle that new dopamine neurons implanted directly into the forebrain can provide significant relief from motor symptoms in some patients. Although the approach has been far from universally successful at the clinical level, more than 30 years of basic and clinical research in this area has led to a detailed understanding of the in vivo properties of foetal tissue grafts and key principles underlying successful therapeutic impact.

The work in this thesis focusses predominantly on promoting brain repair through cell transplantation. A major component of my PhD involved developing and extensively characterizing the phenotype of a focal model of ischemia as well as assessing functional and structural repair of the brain after transplantation. This work involved extensive behavioral testing during 9 months of graft integration and detailed histological examination of the graft and host tissue. In an additional project, I have examined the immunological response that occurs when transplanting neural progenitors within and across strains of mice, as well as into immune-compromised animals – findings that hold important implications for the design and interpretation of pre-clinical cell transplantation studies. Finally, I conducted a study addressing the role of meningeal cells in the development of dopamine neurons in the midbrain, demonstrating that these cells secrete chemokines that influence differentiation and axon guidance – knowledge that I subsequently demonstrated could impact on the integration of transplanted neurons in an animal model of PD.