Extracellular Vesicle-Shuttled mRNA in Mesenchymal Stem Cell Communication

Abstract

Mesenchymal stem cells (MSC) are multipotent cells able to differentiate into several cell types, hence providing cell reservoirs for therapeutic applications. The absence of detectable MSC homing at injury sites suggests that paracrine functions could, at least in part, be mediated by extracellular vesicles (EVs); EVs are newly identified players that are studied mainly as predictive or diagnostic biomarkers. Together with their clinical interests, EVs have recently come to the fore for their role in cell-to-cell communication. In this context, we investigated gene-based communication mechanisms in EVs generated by bone marrow and umbilical cord blood MSC (BMMSC and CBMSC, respectively). Both MSC types released vesicles with similar physical properties, although CBMSC were able to secrete EVs with faster kinetics. A pattern of preferentially incorporated EV transcripts was detected with respect to random internalization from the cytosol, after a validated normalization procedure was established. In the paradigm where EVs act as bioeffectors educating target cells, we demonstrated that kidney tubular cells lacking IL-10 expression and exposed to BMMSC-EVs and CBMSC-EVs acquired the IL-10 mRNA, which was efficiently translated into the corresponding protein. These findings suggest that horizontal mRNA transfer through EVs is a new mechanism in the MSC restoring ability observed in vivo that is here further demonstrated in an in vitro rescue model after acute cisplatin injury of tubular cells. Stem Cells 2017;35:1093-1105.

Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model

“…A number of studies have demonstrated the beneficial effects of MSC-EVs in vitro and in animal models of lung, kidney, and liver diseases [37,38]. Furthermore, several studies have shown that EVs exert their therapeutic effects by transferring their mRNA to diseased cells [20,29,39,40]. In this study, the anti-influenza virus activity of MSC-EVs in lung epithelial cells was mediated by their mRNA content as pretreatment of EVs with RNase enzyme abrogated the anti-influenza virus activity of EVs.…”

Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use

“…It can be envisaged that EVs or VSFs of unmanipulated or engineered human cells represent the therapeutically active substance of these biologic drugs [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. To make these therapeutics available for patients in the future, it is necessary to develop scalable, reproducible and good manufacturing practice (GMP)-compliant manufacturing protocols while recognizing the benefit of regulatory frameworks.…”

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

“…Since the pure isolation of different EV subpopulations according to their intracellular origin is not yet resolved, EVs are often categorized based on their size as small and large EVs . EVs transfer a wide array of biologically important molecules, such as proteins, lipids, mRNAs, and miRNAs in a concentrated form when they target the recipient cells, and the roles of mesenchymal stem cell‐derived and mesenchymal stromal cell‐derived EVs, for example, have already been intensively studied …”