Mesenchymal stem cells versus their extracellular vesicles in treatment of liver fibrosis: Is it possible to compare?

Abstract

Liver fibrosis (LF) is a worldwide health problem that is associated with a range of complications and high mortality. Due to the scarcity of liver donors, mesenchymal stem cell (MSC) therapy emerged as an alternative therapeutic strategy. However, it is widely accepted that most of the transplanted MSCs exhibit their therapeutic impact mainly via a bystander paracrine (medicinal) capacity. In addition to their secretory proteins, MSCs also produce various types of extracellular vesicles (EVs) that are classified into three main subtypes: microvesicles, exosomes and apoptotic bodies. Thanks to their peculiar cargo composition (e.g., proteins, lipids, and nucleic acids), EVs serve as an advantageous candidate for cell-free therapy. Recently, MSC-derived EVs (MSC-EVs) have gained the podium due to their regenerative and immunomodulatory effect. In mitigation/treatment of LF, a plethora of recent studies have shown the anti-inflammatory, anti-fibrotic and cytoprotective effects of both MSCs and MSC-EVs in various in vitro and in vivo models of LF. However, despite the limited evidence, we sought in this mini review to sort out the established data and formulate several challenging questions that must be answered to pave the way for further clinical applications. One of the major questions to ask is “Which is the best therapeutic approach, MSCs or MSC-EVs?” We tried to highlight how difficult it might be to compare the two approaches while our understanding of both candidates is still deficient. Among the major obstacles against such comparison is the inaccurate equivalent dose determination, the unknown in vivo behavior, and the undetermined lifespan/fate of each. Currently, the fields of MSCs and MSC-EVs seem to be rich in ideas but lacking in appropriate technologies to test these ideas. Nevertheless, continuous efforts are likely to help resolve some of the challenges listed here.