Abstract
BackgroundAs pharmacological therapies have largely failed so far, stem cell therapy has recently come into the focus of ALS research. Neuroprotective potential was shown for several types of stem and progenitor cells, mainly due to release of trophic factors. In the present study, we assessed the effects of intracerebroventricular injection of glucagon-like peptide 1 (GLP-1) releasing mesenchymal stromal cells (MSC) in mutant SOD1 (G93A) transgenic mice.Methodology/Principal FindingsTo improve the neuroprotective effects of native MSC, they had been transfected with a plasmid vector encoding a GLP-1 fusion gene prior to the injection, as GLP-1 was shown to exhibit neuroprotective properties before. Cells were encapsulated and therefore protected against rejection. After intracerebroventricular injection of these GLP-1 MSC capsules in presymptomatic SOD1 (G93A) mice, we assessed possible protective effects by survival analysis, measurement of body weight, daily monitoring and evaluation of motor performance by rotarod and footprint analyses. Motor neuron numbers in the spinal cord as well as the amount of astrocytosis, microglial activation, heat shock response and neuronal nitric oxide synthase (nNOS) expression were analyzed by immunohistological methods. Treatment with GLP-1 producing MSC capsules significantly prolonged survival by 13 days, delayed symptom onset by 15 days and weight loss by 14 days and led to significant improvements in motor performance tests compared to vehicle treated controls. Histological data are mainly in favour of anti-inflammatory effects of GLP-1 producing MSC capsules with reduced detection of inflammatory markers and a significant heat shock protein increase.Conclusion/SignificanceIntracerebroventricular injection of GLP-1 MSC capsules shows neuroprotective potential in the SOD1 (G93A) mouse model.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which causes death of motor neurons in the cortex, brain stem and spinal cord
In a transgenic mouse model expressing a mutant form of superoxide dismutase 1 (SOD1) carrying the Gly93 R Ala substitution, progressive death of motor neurons occurs in the ventral horn region of the lumbar spinal cord and the mice develop a phenotype similar to ALS [3]
A previous study assessed the effect of intraspinal injection of mesenchymal stromal cells (MSC) in an ALS rodent model: the authors showed moderate improvements in motor function and survival which were attributed to anti-inflammatory and neurotrophic effects of MSC [30]
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which causes death of motor neurons in the cortex, brain stem and spinal cord. In a transgenic mouse model expressing a mutant form of SOD1 carrying the Gly R Ala substitution, progressive death of motor neurons occurs in the ventral horn region of the lumbar spinal cord and the mice develop a phenotype similar to ALS [3]. Recent studies have demonstrated that stem cell transplantation presents a novel therapeutic approach for a variety of neurological diseases (for review see [5]). Neuroprotective potential was shown for several types of stem and progenitor cells, mainly due to release of trophic factors. We assessed the effects of intracerebroventricular injection of glucagon-like peptide 1 (GLP-1) releasing mesenchymal stromal cells (MSC) in mutant SOD1 (G93A) transgenic mice
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