Switching Roles: Beneficial Effects of Adipose Tissue-Derived Mesenchymal Stem Cells on Microglia and Their Implication in Neurodegenerative Diseases

Abstract

Neurological disorders, including neurodegenerative diseases, are often characterized by neuroinflammation, which is largely driven by microglia, the resident immune cells of the central nervous system (CNS). Under these conditions, microglia are able to secrete neurotoxic substances, provoking neuronal cell death. However, microglia in the healthy brain carry out CNS-supporting functions. This is due to the ability of microglia to acquire different phenotypes that can play a neuroprotective role under physiological conditions or a pro-inflammatory, damaging one during disease. Therefore, therapeutic strategies focus on the downregulation of these neuroinflammatory processes and try to re-activate the neuroprotective features of microglia. Mesenchymal stem cells (MSC) of different origins have been shown to exert such effects, due to their immunomodulatory properties. In recent years, MSC derived from adipose tissue have been made the center of attention because of their easy availability and extraction methods. These cells induce a neuroprotective phenotype in microglia and downregulate neuroinflammation, resulting in an improvement of clinical symptoms in a variety of animal models for neurological pathologies, e.g., Alzheimer’s disease, traumatic brain injury and ischemic stroke. In this review, we will discuss the application of adipose tissue-derived MSC and their conditioned medium, including extracellular vesicles, in neurological disorders, their beneficial effect on microglia and the signaling pathways involved.

Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease

“…The treatment of AD model mice with BMSCs was shown to improve synaptic density, alleviate inflammation within astrocytes, and reduce the M1 microglia ratio. The same function was found in EVs secreted by adipose tissue-derived mesenchymal stem cells [119].…”

Mesenchymal Stem Cells Applications in Alzheimer's Disease

“…When there is an injury in the brain or persistent triggers, microglia can produce excessive inflammation that can harm the brain. 21 The ability of the microglia to switch from proinflammatory (with a round morphology in vitro) to neuroprotectiveness (elongated shape) makes it an excellent therapeutic focus in neuroinflammatory diseases because it aims to maintain microglia in a neuroprotective state that supports the CNS by influencing their inflammatory condition. Aβ accumulation (a pathological hallmark of AD) can trigger the proinflammatory state.…”

Microglia-mediated neuroinflammation and neuroplasticity after stroke

“…Exosomes from hUC-MSCs have been shown to repress I/R-induced pyroptosis in microglia and mitigate subsequent neuronal injury (Hu et al, 2021 ) via enhancement of FOXO3a-dependent mitophagy. AD-MSCs and BM-MSCs-derived exosomes can communicate with microglia, alter the morphology of microglia and attenuate microglia pro-inflammatory activation, consequently alleviating neuroinflammation and improving functional recovery (Sanchez-Castillo et al, 2022 ). Zhao et al ( 2020 ) found that exosomes from MSCs overexpress miR-223-3p, which promoted M2 microglia transformation via inhibition of the cysteinyl leukotriene receptor 2 (CysLT2R) pathway.…”