Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents

Abstract

Extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells (MSCs) have been found to promote comparable therapeutic activities as MSCs themselves. In a variety of in vivo models, it has been observed that they suppress pro-inflammatory processes and reduce oxidative stress and fibrosis. By switching pro-inflammatory into tolerogenic immune responses, MSC-EVs very likely promote tissue regeneration by creating a pro-regenerative environment allowing endogenous stem and progenitor cells to successfully repair affected tissues. Accordingly, MSC-EVs provide a novel, very promising therapeutic agent, which has already been successfully applied to humans. However, the MSC-EV production process has not been standardized, yet. Indeed, a collection of different protocols has been used for the MSC-EV production, characterization and application. By focusing on kidney, heart, liver and brain injuries, we have reviewed the major outcomes of published MSC-EV in vivo studies.

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…In fact, through preconditioning or genetic manipulation of neural cells, their exosome secretion profile can be modified [205,215]. Of note, hypoxia and endothelial activation may be reflected in RNA and protein exosome composition [226,227].…”

“…Their ability to transport molecules and to target specific cell Traumatic Brain Injury -Pathobiology, Advanced Diagnostics and Acute Managementpopulations raised possibilities for their development as therapeutic tools [212][213][214]. MSC-EVs seem to exert positive impacts on tissue-specific stem cells, promote angiogenesis, and suppress oxidative stress and fibrosis, and, noteworthy, may suppress pro-inflammatory responses in brain injury [215,216]. Indeed, it was shown that MSC-EVs are able to convert M1 into M2 macrophages and, therefore, by switching pro-inflammatory into tolerogenic environments, MSC-EV administration might promote regenerative processes [170,205,212,215,[217][218][219][220][221].…”

“…MSC-EVs seem to exert positive impacts on tissue-specific stem cells, promote angiogenesis, and suppress oxidative stress and fibrosis, and, noteworthy, may suppress pro-inflammatory responses in brain injury [215,216]. Indeed, it was shown that MSC-EVs are able to convert M1 into M2 macrophages and, therefore, by switching pro-inflammatory into tolerogenic environments, MSC-EV administration might promote regenerative processes [170,205,212,215,[217][218][219][220][221]. These therapeutic potentials position EVs as highly competitive alternatives to stem cells, as the EVs are likely to be safer than their parental secreting stem cells [212].…”

“…Regarding the brain, impacts of MSC-EV treatment were mainly studied in models for ischemic stroke and TBI and reduced apoptosis rates in affected brains, while promoted angiogenesis and neurogenesis [175-177, 215, 231-236]. Both systemic pro-inflammatory and neuroinflammatory cues were reduced following MSC-EV treatment [107,215].…”

“…Exosomes are endosome-derived small membrane nanosized vesicles (30-100 nm in diameter) generated by almost all cell types and released into extracellular fluids, playing a pivotal role in intercellular communication [178,215]. MSC is the most prolific exosome producer among the cell types known to produce exosomes [204,222].…”