ABSTRACT
Title
Intravenous mesenchymal stem cells improve survival and motor functions in symptomatic mutant SOD1/G93A mice
Authors
M. Milanese 1, T. Bonifacino 1, F. Giribaldi 1, M.C. Principato 2, S. Morando 2, S. Casazza 2, D. Giunti 2, L. Vergani 3, E. Carminati3, A. Uccelli 2, A. Voci 3, G. Bonanno 1.
1Department of Experimental Medicine, Pharmacology and Toxicology Section, and Centre of Excellence for Biomedical Research, University of Genova, Italy.
2Department of Neuroscience, Neurology Section, University of Genoa, Italy.
3 Department of Biology, University of Genoa, Italy.
1Department of Experimental Medicine, Pharmacology and Toxicology Section, and Centre of Excellence for Biomedical Research, University of Genova, Italy.
2Department of Neuroscience, Neurology Section, University of Genoa, Italy.
3 Department of Biology, University of Genoa, Italy.
Abstract
Amyotrophic lateral sclerosis (ALS) is a chronic neuromuscular disorder clinically characterized by muscle wasting, weakness and spasticity reflecting a progressive degeneration of upper and lower motor neurons. The cause of ALS is largely obscure and the lack of knowledge of the mechanisms of neuronal death has impaired the establishment of efficacious therapies.
Mesenchymal stem cells (MSC), a subset of adult stem cells derived from the bone marrow stroma, have generated much enthusiasm as possible cell source for tissue repair, including the nervous system. Recent studies have shown that MSC can also modulate immune responses and exert an anti-apoptotic effect on different cells including neurons.
We studied here the effects of MSC administration in mice expressing mutant human super oxide dismutase (SOD1) with a G93A substitution [SOD1/G93A(+)], a transgenic animal model of ALS.MSCs (106 cells/animal, i.v.) were injected at day 90, after the onset of the first disease symptoms. Saline injected SOD1/G93A(+) were used as controls.
After i.v injection, a few luciferase-labeled MSCs were detected inside the mice spinal cord. MSC-treated mice exhibited a statistically significant prolonged survival time compared to saline injected controls. Such effect was associated with a significant improvement of the performance in behavioral motor tests. Amelioration of relevant spinal cord histological parameters was observed, irrespective of neuronal trans-differentiation. MSCs also reduced oxidative stress in spinal cord of SOD1/G93A(+) mice: metallothionein-1, -2, and -3 mRNAs were up-regulated in during disease progressionand MSC administration almost restored normal expression levels. Moreover, MSCs reduced the activity of glutathione-S-transferase, which was elevated inSOD1/G93A(+) mice.Studying neurotransmitter release, we have previously found that glutamate exocytosis is enhanced in the spinal cord of SOD1/G93A(+) mice. Interestingly, the MSC treatment abolished this extra-release of the excitatory amino acid.
We can conclude that the treatment with MSCs significantly improved survival expectation and motor abilities and that these effects are supported by beneficial modifications of a number of biochemical, functional and histological parameters. Therefore, MSCs can be proposed as an appealing therapeutic opportunity for ALS, although the effect does not seem to rely on tissue repair.
Mesenchymal stem cells (MSC), a subset of adult stem cells derived from the bone marrow stroma, have generated much enthusiasm as possible cell source for tissue repair, including the nervous system. Recent studies have shown that MSC can also modulate immune responses and exert an anti-apoptotic effect on different cells including neurons.
We studied here the effects of MSC administration in mice expressing mutant human super oxide dismutase (SOD1) with a G93A substitution [SOD1/G93A(+)], a transgenic animal model of ALS.MSCs (106 cells/animal, i.v.) were injected at day 90, after the onset of the first disease symptoms. Saline injected SOD1/G93A(+) were used as controls.
After i.v injection, a few luciferase-labeled MSCs were detected inside the mice spinal cord. MSC-treated mice exhibited a statistically significant prolonged survival time compared to saline injected controls. Such effect was associated with a significant improvement of the performance in behavioral motor tests. Amelioration of relevant spinal cord histological parameters was observed, irrespective of neuronal trans-differentiation. MSCs also reduced oxidative stress in spinal cord of SOD1/G93A(+) mice: metallothionein-1, -2, and -3 mRNAs were up-regulated in during disease progressionand MSC administration almost restored normal expression levels. Moreover, MSCs reduced the activity of glutathione-S-transferase, which was elevated inSOD1/G93A(+) mice.Studying neurotransmitter release, we have previously found that glutamate exocytosis is enhanced in the spinal cord of SOD1/G93A(+) mice. Interestingly, the MSC treatment abolished this extra-release of the excitatory amino acid.
We can conclude that the treatment with MSCs significantly improved survival expectation and motor abilities and that these effects are supported by beneficial modifications of a number of biochemical, functional and histological parameters. Therefore, MSCs can be proposed as an appealing therapeutic opportunity for ALS, although the effect does not seem to rely on tissue repair.