Intravenous Mesenchymal Stem Cells Improve Survival and Motor Function in Experimental Amyotrophic Lateral Sclerosis

Abstract

Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 10 6 ) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [ 3 H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase-and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [ 3 H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.

Mesenchymal stem cells for the treatment of neurological diseases: Immunoregulation beyond neuroprotection

“…Intravenous administration of allogeneic MSCs after the onset of motor symptoms prolonged the life span of SOD-G93A mice [94]. Injected MSCs scantly homed to the CNS, but a significant reduction of accumulation of ubiquitin agglomerates and of activated astrocytes and microglia was observed in the spinal cord of MSC-treated SOD1/G93A mice, together with a significant inhibition of the excessive release of glutamate [94]. Similarly, an impact on microglial phenotype with increased percentage of ramified, resting cells and a decreased number of activated cells upon intrathecal MSC treatment after disease onset was observed by Boido and coworkers [95].…”

“…Intravenous administration of allogeneic MSCs after the onset of motor symptoms prolonged the life span of SOD-G93A mice [94]. Injected MSCs scantly homed to the CNS, but a significant reduction of accumulation of ubiquitin agglomerates and of activated astrocytes and microglia was observed in the spinal cord of MSC-treated SOD1/G93A mice, together with a significant inhibition of the excessive release of glutamate [94].…”

Clinical experience with stem cells and other cell therapies in neurological diseases

“…In the SOD1 animal model, injection of MSC intrathecally decreased motor neuron loss in the lumbar spinal cord, preserved motor function, and extended survival. In a recent study, MSC were injected intravenously in an ALS mouse model expressing SOD1 carrying the G93A mutation and showed to improve the survival and motor functions [81]. In the same study researches observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of treated mice and no changes in the number of choline acetyltransferase and glutamate transports type 1-possitive cells [81].…”

“…In a recent study, MSC were injected intravenously in an ALS mouse model expressing SOD1 carrying the G93A mutation and showed to improve the survival and motor functions [81]. In the same study researches observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of treated mice and no changes in the number of choline acetyltransferase and glutamate transports type 1-possitive cells [81]. Mazzini et al [37], transplanted autologous bone marrow MSC into the high thoracic spinal cord in 10 ALS patients.…”

Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research

“…This provides support to the hypothesis that the restoring effects of transplanted cells in not due to cell replacement per se but, rather, it is associated with the production and release of circulating protective factors that may act both ad the CNS and PNS levels. In fact it has been shown that implanted MSCs release a series of cytokines and chemokines with anti-inflammatory properties that could be responsible of the functional improvement of mouse models of motor neuron degenerative disorder (Bigini et al, 2011;Uccelli et al, 2012).…”