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Laura Grabel


Molecular Biology and Biochemistry




Cell-replacement therapy is an appealing option for the treatment of neurodegenerative disease. Embryonic stem cells (ESCs) offer a virtually unlimited source of neural progenitors, a fundamental cell type for transplantation into the nervous system; however, before they can be applied, strategies involving ESC-derived neural progenitors (ESNPs) require thorough consideration of the interactions between transplanted ESNPs and the host tissue. In studies of endogenous (tissue-specific) and ESC-derived neural stem cell transplantation, researchers have documented a significant relationship between graft cells and the neurovasculature. In this thesis, we use an in vitro approach to investigate several of the observed interactions between human ESNPs and blood vessel-forming mouse brain endothelial cells (BECs).

We observe dramatic morphological differences between ESNPs cultured alone and ESNPs cultured in the presence of BECs, and we also note endothelial reorganization that appears responsive to the presence of ESNPs. In co-culture with BECs, neuronal morphology and gene expression are altered, suggesting inhibited neuronal differentiation. We examine the molecular mechanisms underlying hESNP-BEC adhesion and identify a role for the laminin receptor α6β1 integrin. Lastly, we find that BEC-secreted chemoattractants direct the migration of hESNPs and that the CXCL12 peptide is a viable candidate. These in vitro findings support an in vivo model in which blood vessel-secreted factors attract transplanted hESNPs, inducing α6β1-mediated hESNP-vessel adhesion. hESNPs directly contacting the vasculature may develop altered morphologies and exhibit inhibited maturation, characteristic of neural stem cells within the neurogenic niches. These mechanisms and consequences of hESNP-blood vessel interactions are necessary considerations in the design of transplantation strategy.



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