Human Skeletal Muscle Stem Cell Antiinflammatory Activity Ameliorates Clinical Outcome in Amyotrophic Lateral Sclerosis Models

Abstract

Mesenchymal stem cell (MSC) therapy is considered one of the most promising approaches for treating different neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). We previously characterized a subpopulation of human skeletal muscle-derived stem cells (SkmSCs) with MSC-like characteristics that differentiate into the neurogenic lineage in vitro. In the present study, we evaluated the SkmSC therapeutic effects in the most characterized model of spontaneous motor neuron degeneration, the Wobbler (Wr) mouse. Before evaluating the therapeutic efficacy in the Wr mouse, we followed the route of SkmSCs at different times after intracerebroventricular injection. Two exogenous tracers, superparamagnetic iron oxide (SPIO) nanoparticles and Hoechst 33258, were used for the in vivo and ex vivo tracking of SkmSCs. We found that the loading of both Hoechst and SPIO was not toxic and efficiently labeled SkmSCs. The magnetic resonance imaging (MRI) system 7 Tesla allowed us to localize transplanted SkmSCs along the whole ventricular system up to 18 wks after injection. The ex vivo Hoechst 33258 visualization confirmed the in vivo results obtained by MRI analyses. Behavioral observations revealed a fast and sustained improvement of motor efficacy in SkmSC-treated Wr mice associated with a relevant protection of functional neuromuscular junctions. Moreover, we found that in SkmSC-treated Wr mice, a significant increase of important human antiinflammatory cytokines occurred. This evidence is in accordance with previous findings showing the bystander effect of stem cell transplantation in neurodegenerative disorders and further strengthens the hypothesis of the possible link between inflammation, cytotoxicity and ALS.

The wobbler mouse, an ALS animal model

“…“Human skeletal muscle-derived stem cells (SkmSCs)” showed a positive effect, after implantation in the brain lateral ventricles of wobbler mice. Like HuCB-MNCs, transplanted SkmSCs did not reach the ventral horns of cervical spinal cords, but magnetic resonance imaging (MRI) showed that some clusters of cells migrated in the spinal parenchyma and the signal was maintained up to 18 weeks after transplantation (Canzi et al 2012). The evidence of a marked expression of specific human anti-inflammatory cytokines in the brain of transplanted wobbler mice seems to confirm the hypothesis that a bystander effect of soluble factors, released by SkmSCs, even far from the affected areas, might play a neuroprotective role.…”

Application of Iron Oxide Nanoparticles in the Diagnosis and Treatment of Neurodegenerative Diseases With Emphasis on Alzheimer’s Disease

“…The therapeutic efficacy of SkmSCs (subpopulation of human skeletal muscle-derived stem cells) with MSC-like features was evaluated after intracerebroventricular injection to the Wr mouse (Wobbler mouse, the most typical model of spontaneous motor neuron degeneration) by Canzi et al (2012). The research team confirmed that MRI can visualize stem cells and follow their migration after transplantation in the CNS of rodents (Canzi et al, 2012).…”

Concise Review: Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future

“…Finally, the multifaceted mechanisms and variety of cell types proposed to contribute to ALS pathogenesis support cellular therapy development using non-neuronal progenitors. Intracerebroventricular injection of skeletal muscle stem cells induces anti-inflammatory cytokine production, improved motor function, and protection of neuromuscular junctions in wobbler mice [57]. Intraspinal transplantation of glialrestricted progenitor cells into the cervical spinal cord of G93A-SOD1 rats, as a means to increase astrocyte numbers in spinal cord regions controlling critical respiratory function, attenuates motor neuron loss, slows respiratory functional declines, and improves survival by approximately 17 days [58].…”

“…Upon clinical translation, however, more sophisticated techniques to identify and follow the fate of grafted cells will be required. For instance, the labeling of cells with superparamagnetic iron oxide nanoparticles or reporter genes allows cell graft tracking using advanced imaging technologies [28,57,[90][91][92][93][94][95]. Notably, these approaches can provide insight into the migratory potential of grafted cells following systemic or targeted injections, as demonstrated in both a large animal and human trials [73,86].…”