Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol

Abstract

BackgroundOver the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury.MethodsA systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles.DiscussionThis systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.

Mesenchymal stromal cell variables influencing clinical potency: the impact of viability, fitness, route of administration and host predisposition

“…Considering that the MSC-dependent mechanism of action is anchored in its secretome [42], a cogent argument can be made that the best cell therapy is done without any cells, but rather using elements of the secretome, such as components derived from extracellular vesicles such as exosomes [43]. Indeed, characterization and translational development of MSC-derived exosomes [44,45] and related extracellular vesicles are of great interest [46,47].…”

Preclinical Studies of MSC-Derived Extracellular Vesicles to Treat or Prevent Graft Versus Host Disease: a Systematic Review of the Literature

“…In our recent comprehensive systematic scoping review of methods and outcome reporting in all preclinical studies of MSC-derived EVs, a total of 208 studies were identified [ 19 , 20 ] and an updated search conducted December 2018 identified 284 additional records that underwent screening for potential relevance and eligibility, identifying 113 additional studies. Amongst these 321 studies, four addressed GVHD treatment and/or prevention and were included in the quantitative and in-depth analysis described in this report (see Fig.…”

“…We identified eligible studies from a comprehensive systematic scoping review performed in May 2018 and updated in December 2018 [ 20 ] (registered April 12, 2019 on PROSPERO at www.crd.york.ac.uk/prospero , protocol: CRD42019123918). In brief, this larger scoping review included all studies using MSC-EVs in preclinical animal models of disease, organ injury, tumor growth or altered immune response.…”

Extracellular vesicle therapy for retinal diseases

“…As more studies demonstrate that EV have an active and potentially therapeutic role in the body, as opposed to only a passive one (Joo et al, 2020;Tieu et al, 2019), it is anticipated that there will be more clinical trials focusing on their clinical potential rather than their role solely as biomarkers.…”