Reversal of Dopaminergic Degeneration in a Parkinsonian Rat following Micrografting of Human Bone Marrow-Derived Neural Progenitors
Open Access
- 1 July 2009
- journal article
- Published by SAGE Publications in Cell Transplantation
- Vol. 18 (7), 801-814
- https://doi.org/10.3727/096368909x470801
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease characterized by the selective loss of dopaminergic (DA) neurons in the midbrain. Various types of stem cells that have potential to differentiate into DA neurons are being investigated as cellular therapies for PD. Stem cells also secrete growth factors and therefore also may have therapeutic effects in promoting the health of diseased DA neurons in the PD brain. To address this possibility in an experimental model of PD, bone marrow-derived neuroprogenitor-like cells were generated from bone marrow procured from healthy human adult volunteers and their potential to elicit recovery of damaged DA axons was studied in a partial lesion rat model of PD. Following collection of bone marrow, mesenchymal stem cells (MSC) were isolated and then genetically modified to create SB623 cells by transient transfection with the intracellular domain of the Notch1 gene (NICD), a modification that upregulates expression of certain neuroprogenitor markers. Ten deposits of 0.5 μl of SB623 cell suspension adjusted from 6,000 to 21,000 cells/μl in PBS or PBS alone were stereotaxically placed in the striatum 1 week after the nigrostriatal projection had been partially lesioned in adult F344 rats by injection of 6-hydroxydopamine (6-OHDA) into the striatum. At 3 weeks, a small number of grafted SB623 cells survived in the lesioned striatum as visualized by expression of the human specific nuclear matrix protein (hNuMA). In rats that received SB623 cells, but not in control rats, dense tyrosine hydroxylase immunoreactive (TH-ir) fibers were observed around the grafts. These fibers appeared to be rejuvenated host DA axons because no TH-ir in soma of surviving SB623 cells or coexpression of TH and hNuMA-ir were observed. In addition, dense serotonin immunoreactive (5-HT-ir) fibers were observed around grafted SB623 cells and these fibers also appeared to be of the host origin. Also, in some SB623 grafted rats that were sacrificed within 2 h of dl-amphetamine injection, hot spots of c-Fos-positive nuclei that coincided with rejuvenated dense TH fibers around the grafted SB623 cells were observed, suggesting increased availability of DA in these locations. Our observations suggest that NICD-transfected MSC hold potential as a readily available autologous or allogenic cellular therapy for ameliorating the degeneration of DA and 5-HT neurons in PD patients.Keywords
This publication has 72 references indexed in Scilit:
- In Vitro and In Vivo Characterization of Neurally Modified Mesenchymal Stem Cells Induced by Epigenetic Modifiers and Neural Stem Cell EnvironmentStem Cells and Development, 2008
- Basic Fibroblast Growth Factor Modulates Density of Blood Vessels and Preserves Tight Junctions in Organotypic Cortical Cultures of Mice: A NewIn VitroModel of the Blood–Brain BarrierJournal of Neuroscience, 2007
- Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primatesGene Therapy, 2005
- Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivoGene Therapy, 2003
- Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia modelThe Annals of Thoracic Surgery, 2003
- Persephin-Overexpressing Neural Stem Cells Regulate the Function of Nigral Dopaminergic Neurons and Prevent Their Degeneration in a Model of Parkinson's DiseaseMolecular and Cellular Neuroscience, 2002
- Remyelination of the Rat Spinal Cord by Transplantation of Identified Bone Marrow Stromal CellsJournal of Neuroscience, 2002
- Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brainNature, 1995
- Reversal of hemiparkinsonian syndrome in nonhuman primates by amnion implantation into caudate nucleusJournal of Neurosurgery, 1994
- Trophism, Transplantation, and Animal Models of Parkinson's DiseaseExperimental Neurology, 1993