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Functional effects of transplanted embryonic stem cell-derived neural aggregates overexpressing the neural cell adhesion molecule L1 in the MPTP model of Parkinson's disease and in a spinal cord injury model in Mus musculus (Linnaeus, 1758)
Funktionelle Effekte von transplantierten aus embryonalen Stammzellen hervorgegangenen neuralen Aggregaten, die das Zelladhäsionsmolekül L1 überexprimieren im MPTP-Modell der Parkinson´schen Erkrankung und im Modell der Rückenmarksverletzung ...
(2009) Stem Cells. 2008 Aug;26(8):1973-84. Epub 2008 May 22. J Neurosci. 2006 Nov 8;26(45):11532-9.
Dokument 1.pdf (8.928 KB)
Zell-Adhäsionsmolekül , Stammzelle , Zelltransplantation , Regeneration , Rückenmarksverletzung
Freie Schlagwörter (Englisch):
Schachner, Melitta (Prof. Dr.)
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
Adhesion molecules play important roles in the development and regeneration of the central and peripheral nervous system. The neural cell adhesion molecule L1 is a cell molecule belonging to the immunoglobulin superfamily. It can favor axonal growth in an inhibitory environment, promote neurite outgrowth, neuronal migration and survival.
Embryonic stem cells (ESC) derived from the inner cell mass of the blastocyst, have the ability to differentiate into cells of all three germ layers, including neural precursor cells. In this study, a murine embryonic stem cell line constitutively expressing L1 at all stages of differentiation was used to monitor the molecules effects on stem cell survival, differentiation, and ability to influence functional recovery in a murine model of Parkinson’s disease and in a spinal cord injury model. Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease with millions of people affected worldwide. In PD, the progressive degeneration of mesencephalic dopaminergic neurons of the nigrostriatal system results in a depletion of dopamine that creates severe motor dysfunction. One experimental approach is to enhance the number of dopaminergic neurons to restore the control of movement and motor activities. Although implantation of fetal dopaminergic neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. Nowadays, stem cell replacement has emerged as a novel therapeutic strategy for Parkinson’s disease.
Spinal cord injury is an insult to the spinal cord resulting in a change, either temporary or permanent, in its normal motor, sensory, or autonomic function. Causes
include motor vehicle accidents, violence, falls, and recreational activities. Traumatic spinal cord injury immediately leads to irreversible primary tissue damage. Secondary damage follows afterwards. Current therapeutic approaches to spinal cord injury are inadequate. Therefore, increasing attention has been placed on the role of CNS stem
cells in spinal cord repair, including embryonic stem cells.
This study applied a new ESC differentiation protocol. ES cell-derived substrate-adherent neural aggregates (SENAs) that consist predominantly of neurons (>90%) and radial glial cells (>8%) were generated applying this procedure. Female C57BL/6J mice were intraperitoneally injected with mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) to selectively deplete dopaminergic neurons. SENAs were unilaterally transplanted into the striatum or the substantia nigra four days after MPTP injection.
One month after transplantation, the mice grafted with L1 overexpressing SENAs showed a significant asymmetrical rotation bias to the grafted side after injection of apomorphine when compared to either mice grafted with control SENAs or sham-injected with PBS up to 10 weeks after transplantation. The behavioral change indicates that L1 overexpressing SENAs can improve locomotor function after
MPTP-induced loss of doparminergic neurons. Morphological analysis revealed that L1 overexpressing SENAs showed enhanced neuronal differentiation and increased survival of transplanted cells in the lesioned striatum when compared to control SENAs. Transplantation of L1 overexpressing, but
not control, SENAs led to enhanced numbers of endogenous dopaminergic neurons in the host substantia nigra indicating a beneficial effect of L1 on endogenous cells.
Moreover, engrafted L1 overexpressing SENAs enhanced striatal the dopamine level when compared to control SENAs but did not influence the level of GABA (Gamma-aminobutyric acid) in the striatum. Furthermore, female C57BL/6J mice were traumatically lesioned by compression at the thoracic (T8-T10) level of the spinal cord. SENAs were transplanted into the spinal cord both rostral and caudal to the lesion site three days later.
Three weeks after transplantation, mice grafted with L1 overexpressing SENAs showed better locomotor function when compared with mice grafted with control SENAs or sham-injected with PBS. This effect was observed up to six weeks after transplantation. Morphological analysis revealed that L1 overexpressing SENAs showed enhanced neuronal differentiation, reduced glial differentiation. These cells also displayed increased viability in the inhibitory environment when compared to control SENAs. Moreover, engrafted L1 overexpressing SENAs rescued host motor neurons and enhanced numbers of catecholaminergic (TH+) nerve fibres distal to the lesion.
Thus, L1 overexpressing SENAs enhance functional recovery in an MPTP model of Parkinson’s disease and in a comression lesion model of spinal cord injury.