Extracellular Microvesicles as Game Changers in Better Understanding the Complexity of Cellular Interactions-From Bench to Clinical Applications

Abstract

Recent research has led to wide acceptance and better understanding of a novel mechanism for cell-cell communication that employs a network of extracellular microvesicles (ExMVs). Derived from the plasma membrane or the endosomal membrane compartment, these small, spherical membrane fragments are secreted from the cell surface or in the process of exocytosis from endosomal membrane compartment and (1) with ligands expressed on their surface directly stimulate target cells in a paracrine manner, (2) transfer cell membrane receptors to target cells or (3) deliver encapsulated messenger RNA, microRNA, proteins and bioactive lipids to target cells. This represents an evolutionarily ancient mechanism by which cells signal their presence in the microenvironment, communicate with each other and affect the biology of neighboring cells. Evidence suggests the pivotal role of ExMVs in almost all biological processes within the body as well as their involvement in certain pathologies. Moreover, liquid biopsies based on deciphering the molecular signature of ExMVs promise to revolutionize laboratory diagnostics. At the same time, there are ongoing attempts to employ them as delivery vehicles for drugs as well as therapeutics in regenerative medicine, oncology and immunotherapy.

Keywords: Cell communication; Exosomes; Extracellular microvesicles; Horizontal transfer of RNA and proteins; Liquid biopsies.

Figure 1. Different possible approaches to generating more efficient pro-regenerative ExMVs

ExMVs for therapeutic purposes could be harvested from large-scale in vitro cultures of producing cell lines—for example, mesenchymal stem cells or induced pluripotent stem cells. Such cell lines may be modified to obtain ExMVs that do not express HLA antigens (Panel A); are enriched in growth factors, cytokines, chemokines, and bioactive lipids that promote regeneration of damaged organs (Panel B); are enriched in mRNA and regulatory miRNA facilitating regeneration of damaged tissues and/or promoting angiogenesis (Panel C); or display on their surface molecules that direct them to, and cause them to be retained in, damaged tissues (Panel D) [adapted from Ratajczak MZ et al; ref. 16].