Systematic review of extracellular vesicle‐based treatments for lung injury: are EVs a potential therapy for COVID‐19?

Abstract

Severe COVID-19 infection results in bilateral interstitial pneumonia, often leading to acute respiratory distress syndrome (ARDS) and pulmonary fibrosis in survivors. Most patients with severe COVID-19 infections who died had developed ARDS. Currently, ARDS is treated with supportive measures, but regenerative medicine approaches including extracellular vesicle (EV)-based therapies have shown promise. Herein, we aimed to analyse whether EV-based therapies could be effective in treating severe pulmonary conditions that affect COVID-19 patients and to understand their relevance for an eventual therapeutic application to human patients. Using a defined search strategy, we conducted a systematic review of the literature and found 39 articles (2014-2020) that reported effects of EVs, mainly derived from stem cells, in lung injury models (one large animal study, none in human). EV treatment resulted in: (1) attenuation of inflammation (reduction of pro-inflammatory cytokines and neutrophil infiltration, M2 macrophage polarization); (2) regeneration of alveolar epithelium (decreased apoptosis and stimulation of surfactant production); (3) repair of microvascular permeability (increased endothelial cell junction proteins); (4) prevention of fibrosis (reduced fibrin production). These effects were mediated by the release of EV cargo and identified factors including miRs-126, −30b-3p, −145, −27a-3p, syndecan-1, hepatocyte growth factor and angiopoietin-1. This review indicates that EV-based therapies hold great potential for COVID-19 related lung injuries as they target multiple pathways and enhance tissue regeneration. However, before translating EV therapies into human clinical trials, efforts should be directed at developing good manufacturing practice solutions for EVs and testing optimal dosage and administration route in large animal models.

A Role for Extracellular Vesicles in SARS-CoV-2 Therapeutics and Prevention

“…Regardless of which method used to isolate and concentrate EVs each method requires standardization in order to optimize reproducibility, purity, and maintenance of EVs' functional properties (Gardiner et al 2016;Khalaj et al 2020).…”

Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development

“…In a systematic review, Khalaj et al [ 198 ] reported that exosomes extracted from mesenchymal stem cells derived from bone marrow or umbilical cord ameliorate lung injury in experimental models by (1) attenuating inflammation (reducing pro-inflammatory cytokine levels, neutrophil infiltration, and macrophage polarization); (2) regenerating alveolar epithelium (by reducing apoptosis and stimulating surfactant production); (3) reducing microvascular permeability (by upregulating endothelial cell junction protein levels); and (4) preventing fibrosis (reducing fibrin production). The authors attributed these differential effects to the release of EV cargoes and identified several of the factors responsible, which included miRs126, -30b, -3p, -145, -27a-3p, syndecan-1, hepatocyte growth factor, and angiopoietin-1 [ 198 ]. Exosomal delivery of miR-146b inhibited tumor growth in a xenograft model of GBM [ 161 , 199 ], and the delivery of anti-miRs against miR-9 (an oncogenic miRNA) to GBM cells increased their susceptibility to chemotherapeutics like temozolomide [ 160 ].…”

Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases—Intravenous Administration versus Inhalation

“…The majority of the reported effects, namely restoration of epithelial and endothelial function by increased cellular repair and decreased rate of apoptosis, higher surfactant production, increased resorption of lung fluid, restoration of tight junctions and reduced fibrin production may be mediated by EVs. EVs are also supposed to be involved in reduction of pro-inflammatory and enhancement of anti-inflammatory cytokine secretion, reduction of neutrophil infiltration and M2 polarization of alveolar macrophages [ 41 ]. Preclinical data identified cell-to-cell contact via programmed death-1 for MSC-T cell interaction, changes in amino acid and lipid metabolism by indoleamine 2,3-dioxygenase (IDO) expression, prostaglandin E2 (PGE2) production, tumor growth factor-beta (TGF-β) and HGF and increased expression of leukocyte protease inhibitor via EGF and HGF as important mechanisms [ 42 ].…”