Abstract
BackgroundThe simultaneous contribution of several etiopathogenic disturbances makes amyotrophic lateral sclerosis (ALS) a fatal and challenging disease. Here, we studied two different cell therapy protocols to protect both central and peripheral nervous system in a murine model of ALS.MethodsSince ALS begins with a distal axonopathy, in a first assay, we performed injection of bone marrow cells into two hindlimb muscles of transgenic SOD1G93A mice. In a second study, we combined intramuscular and intraspinal injection of bone marrow cells. Fluorescence-activated cell sorting was used to assess the survival of the transplanted cells into the injected tissues. The mice were assessed from 8 to 16 weeks of age by means of locomotion and electrophysiological tests. After follow-up, the spinal cord was processed for analysis of motoneuron survival and glial cell reactivity.ResultsWe found that, after intramuscular injection, bone marrow cells were able to engraft within the muscle. However, bone marrow cell intramuscular injection failed to promote a general therapeutic effect. In the second approach, we found that bone marrow cells had limited survival in the spinal cord, but this strategy significantly improved motor outcomes. Moreover, we also found that the dual cell therapy tended to preserve spinal motoneurons at late stages of the disease and to reduce microgliosis, although this did not prolong mice survival.ConclusionOverall, our findings suggest that targeting more than one affected area of the motor system at once with bone marrow cell therapy results in a valuable therapeutic intervention for ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a progressive and selective death of upper and lower motoneurons (MNs) [1]
Bone marrow cells immunophenotypic characterization Adult mouse bone marrow is composed by two main stem cell lineage populations: hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs)
Using Fluorescence-activated cell sorting (FACS) immunophenotyping, we found that mouse bone marrow is mainly composed by mature lineage hematopoietic cells (~ 34%, lineage antibody cocktail (Lin)+) and progenitor cells (~ 55%, Lin−) (Fig. 1a, b)
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a progressive and selective death of upper and lower motoneurons (MNs) [1]. Novel therapies that only target a single factor have largely failed when translated into human clinical trials [9]. These failures suggest that more effective therapeutic approaches should act simultaneously on several targets in order to mediate global neuroprotection. In this way, cell therapy has emerged as a promising way to target several cells and mechanisms involved in ALS.
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