ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

Roberta Bonafede, Raffaella Mariotti, Roberta Bonafede, Raffaella Mariotti

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.

Keywords: ALS therapeutic applications; amyotrophic lateral sclerosis; exosomes; extracellular vesicles; mesenchymal stem cells.

Figures

Figure 1
Figure 1
Pathogenetic mechanisms involved in amyotrophic lateral sclerosis (ALS). The pathophysiological mechanism of the disease appears to be multifactorial and several mechanisms contribute to neurodegeneration. An increase of the neurotransmitter glutamate in the synaptic cleft (glutamate excitotoxicity), due to the impairment of its uptake by astrocytes, leads to an increased influx of Ca2+ ions in the motoneurons. The increased levels of Ca2+ ions, which in physiological conditions could be removed by mitochondria (calcium homeostasis), remain high in the cytoplasm due to mitochondrial dysfunction and can cause neurodegeneration through activation of Ca2+-dependent enzymatic pathways contributing to oxidative stress. Mutant misfolding proteins (such as superoxide dismutase 1 gene (SOD1), chromosome 9 open reading frame 72 (C9orf72), TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) form intercellular aggregates, contribute to an increase of oxidative stress, contribute to mitochondrial dysfunction and could lead to the accumulation of neurofilaments (NFs) and dysfunction of axonal transport. Moreover, activated astrocyte and microglia release inflammatory mediators and toxic factors, contributing to neurotoxicity.
Figure 2
Figure 2
Hypothetical mechanisms of action of exosomes. Exosomes interact with the endothelial cells of the blood-brain barrier (BBB) modifying the integrity of cell junctions and increasing the permeability between cells. This mechanism allows a massive entry of vesicles in the central nervous system (CNS). Once in the CNS, exosomes could interact directly on motoneurons (arrows) modulating different biological processes (such as apoptosis, cell proliferation, gene expression and oxidative stress) or indirectly modifying the local motoneuron environment, acting on glial cells that decrease the release of toxic factor and inflammatory mediators (dotted arrows). These direct and indirect mechanisms of action of exosomes could counteract the pathological mechanisms involved in the disease.

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