ReviewPre-clinical investigation of mesenchymal stromal cell-derived extracellular vesicles: a systematic review
Introduction
Lazarus et al. [1] introduced mesenchymal stromal cell (MSC) therapy in 1995, and 25 years later, MSCs are the most common cells used in cell therapy trials [2]. MSCs possess multi-lineage differentiation potential and exhibit characteristics of stem cells [3]. These cells have a spindle-shaped, plastic-adherent appearance in vitro [4] and can be isolated from fetal tissues and numerous adult tissues [5] and derived from pluripotent stem cells [6]. Despite recent challenges with their use, MSCs are a readily accessible source for cell-based therapies [5,7].
Various animal models of disease have shown that MSCs act via a myriad of paracrine pathways that affect adjacent and distant responder cells and tissues [8]. Among paracrine factors are extracellular vesicles (EVs) that include a variety of nano- to micro-sized membrane-enclosed vesicles called exosomes, microvesicles, microparticles and apoptotic bodies [9].
Beginning with the initial study published by Bruno et al. [10], MSC-derived EVs (MSC-EVs) have been extensively evaluated in various animal models of disease. These efforts are focused on demonstrating that MSC-EVs replicate the beneficial impacts of their parental cells and as such represent a more practical alternative for clinical use. MSC-EVs have been used in the clinical setting [11,12], and there are numerous ongoing clinical trials (NCT03384433, NCT02138331, NCT03608631, NCT03437759, NCT03478410, NCT04313647, NCT04366063, NCT04491240, NCT04493242 and NCT04276987) that are registered at www.clinicaltrials.gov. According to the International Society for Extracellular Vesicles (ISEV), concerns exist about the actual potential of EVs and the lack of transparency in reported studies [9,13]. More specifically, considerations regarding the therapeutic applications of MSC-EVs have been discussed [14,15].
A systematic review published in 2015 [16] provided insights into the treatment of experimental acute kidney injury and myocardial infarction using MSC-EVs as well as the possible benefits observed in animal models of cancer. The majority of pre-clinical studies that have used MSC-EVs have been published since 2015. Therefore, the authors designed the current study to systematically review the literature that has been published over the past decade. In this review, the authors intend to classify and provide a critical discussion of the technical aspects of MSC-EV pre-clinical investigations and shed light on existing preferences in methods of EV isolation and characterization, route of administration, length of follow-up, MSC sources and animal species as disease models.
Section snippets
Search strategy
The search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines [17]. The authors conducted a literature search in the PubMed and Scopus databases for animal models of disease using MSC-EVs as an intervention until August 16, 2020 (see supplementary Figure 1). The search strategy employed the terms (stem cell* OR stromal cell* OR MSC OR mesenchymal in [Title/Abstract] OR “Stromal Cells” OR “Mesenchymal Stromal Cells” OR “Multipotent
Included studies
The authors’ literature search identified 9358 unique citations that were subsequently screened by title and abstract, leaving 951 eligible full-text articles, of which 690 described animal studies wherein MSC-EVs were administered (see supplementary Figure 1). The authors divided the eligible articles into the following categories: autoimmune (n = 10), brain (n = 73), cancer (n = 50), eyes (n = 16), gastrointestinal (n = 19), heart (n = 75), inflammation/transplantation (n = 28), liver
Discussion
Over the past decade, MSC-EVs have emerged as powerful candidates for regenerative medicine and drug delivery applications. The publication of approximately 380 articles in the 20 months prior to the submission of this systematic review indicates a global explosion of interest in MSC-EV therapeutics. Excluding controversies in MSC-EV cancer therapy, this emerging therapy appears to be beneficial in many settings. This may imply the presence of similar healing mechanisms that are common to
Funding
This study was funded by grants provided by the Royan Institute.
Declaration of Competing Interest
The authors have no commercial, proprietary or financial interest in the products or companies described in this article.
Author Contributions
Conception and design of the study: FSh. Acquisition of data: FSh. Analysis and interpretation of data: ArN, SAK, FSh. Drafting or revising the manuscript: All authors. All authors have approved the final article.
Acknowledgments
The authors thank all members of the Extracellular Vesicle Group at the Royan Institute for their helpful deliberations and consultation during this work.
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These authors contributed equally to this work.