Narawadee Choompoo1, Oliver J M Bartley2, Sophie V Precious2, Ngoc-Nga Vinh2, Christian Schnell2, Ana Garcia2, Victoria H Roberton2, Nigel M Williams3, Paul J Kemp2, Claire M Kelly4, Anne E Rosser5. 1. Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; Department of Anatomy, Faculty of Medical Science, Naresuan University, Phisanulok, Thailand. 2. Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK. 3. MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK. 4. Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK. 5. Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK; Wales Brain Repair and Intracranial Neurotherapeutics Unit, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: rosserae@cf.ac.uk.
Abstract
BACKGROUND: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells. RESULTS: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.
BACKGROUND: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells. RESULTS: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.
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