As a novel therapy for neurodegenerative diseases, transplantation of multipotent mesenchymal stromal cells (MSCs) requires extensive optimization in animal models before being implemented in clinical trials. It is a goal of our laboratory to understand the mechanism of action of these cells and to improve their therapeutic efficacy. To address these goals, this study aims to optimize the cell dosage, cell type, administration route and timing, and/or donor age for stem cell therapy in two mouse models of demyelinating diseases: globoid cell leukodystrophy (GLD; Krabbe’s disease) and experimental autoimmune encephalomyelitis (EAE). GLD is a neurodegenerative lysosomal storage disease caused by the deficiency of galactocerebrosidase (GALC). Accumulation of toxic byproducts in myelin producing oligodendrocytes leads to the demyelination of neurons and increase in brain inflammation. The twitcher mouse model of GLD was used to test the therapeutic effects of MSCs after injection through intracerebroventricular (ICV) or intraperitoneal (IP) routes. Weekly MSC IP injections and single IP GALC-transduced MSC injections were performed. Other twitcher mouse cohorts received temporal vein (TV) or intracerebral (IC) injections of GALC-containing adeno-associated virus serotype 9 (AAV9-GALC) with or without IP MSC injections. All GLD affected mice treated with peripheral MSC and/or vector therapy had extended lifespans with improved motor function. The ameliorating effects of MSCs were related to their potent anti-apoptotic and anti-inflammatory effects on the peripheral and central nervous systems. These results indicate a promising future for peripheral administration of MSCs and vectors as non-invasive, adjunct therapies for patients affected with GLD. A similar study was performed using the EAE mouse model of multiple sclerosis (MS), which is a demyelinating disease due to an autoimmune reaction to myelin. The results demonstrated that biological age of the donor reduces the ability of MSCs to alleviate symptoms and improve pathology in the EAE mouse model. Upon transplantation, the young, but not old, MSCs provided neuroprotective effects through immunomodulation and remyelination in the central nervous system (CNS). The age-related therapeutic differences corroborate recent findings that biologic aging occurs in stem cells and highlight the potential need for allogeneic transplantation of MSCs in older MS patients. / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27904 |
| Date | January 2015 |
| Contributors | Ashton Scruggs, Brittni (Author), Bunnell, Bruce A. (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Format | 272 |
| Rights | Copyright is in accordance with U.S. Copyright law |
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