Amyotrophic lateral sclerosis (ALS) is the main motor neuron disease affecting more than 400,000 people worldwide with mortality rate of 92%. There is no cure for ALS and available treatments can only extend the lifespan of the patients in 3 months. Mesenchymal stem cells (MSC) are immunomodulators that regulate cellular processes by either cell-cell contact or their paracrine effect. MSC-released factors such as extracellular vesicles (including microvesicles and exosomes) can modulate different cell functions. Exosomes, specifically, carry nucleic acids, proteins and miRNA that can be uptaken via endocytosis or phagocytosis, altering cell functions. Currently, the stem cell therapeutic approach for treating ALS suggests the use of both MSC and induced pluripotent stem cells as a tool for differentiation into motor neurons. However, their direct transplantation into patients holds a tumorigenic potential. Given that, the project here presented proposes the use of MSC-secretome as a new tool for treating ALS by elucidating how MSC-secreted exosomes can modulate or be modulated by microglia activation status, considering the microglial-neuroinflammatory basis of ALS. For that, we propose to characterize the content of exosomes derived from MSC of different sources, e.g. human umbilical cord, bone marrow and adipose tissue, aiming to demonstrate for the first time how activated microglia - as seen in ALS - can alter MSC secretome and how exosomes can modulate pro-inflammatory microglial cells towards a neuroprotective status. We expect to provide an important clue to use exosomes as a delivery tool to modulate microglia activation status as a new stem cell-based therapy for ALS.
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