Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later

Abstract

Extracellular microvesicles (ExMVs) are part of the cell secretome, and evidence has accumulated for their involvement in several biological processes. Fourteen years ago our team demonstrated for the first time that ExMVs carry functional RNA species and proteins from one cell to another, an observation that opened up the new research field of horizontal transfer of bioactive molecules in cell-to-cell communication. Moreover, the presence of mRNA, noncoding RNA, and miRNA in ExMVs in blood and other biological fluids opened up the possibility of employing ExMVs as new detection markers for pathological processes, and ExMVs became a target for "liquid biopsy" approaches. While ExMV-derived mRNAs may be translated in target cells into appropriate proteins, miRNAs regulate expression of corresponding mRNA species, and both RNA-depended ExMV-mediated mechanisms lead to functional changes in the target cells. Following from this observation, several excellent papers have been published that confirm the existence of the horizontal transfer of RNA. Moreover, in addition to RNA, proteins, bioactive lipids, infectious particles and intact organelles such as mitochondria may follow a similar mechanism. In this review we will summarize the impressive progress in this field-14 years after initial report.

Keywords: Circulating RNA; ExMVs; Exosomes; Horizontal transfer of RNA; Liquid biopsies; RNA; Regenerative medicine.

Fig. 1

Upon activation, every cell type secretes ExMVs. Larger ExMVs (microvesicles) are released from the cell surface by blebbing and budding of the cell membrane, Smaller ExMVs (exosomes) are initiated in endosomes as intraluminal vesicles in multivesicular bodies (MVBs) after endocytosis of pathogens or due to activation of cells by other stimuli, or are generated in the Golgi apparatus during secretion of cell-synthesized proteins

Fig. 2

Different possible approaches to generating more efficient pro-regenerative ExMVs. ExMVs 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 (a), are enriched in growth factors, cytokines, chemokines and bioactive lipids that promote regeneration of damaged organs (b), are enriched in mRNA and regulatory miRNA facilitating regeneration of damaged tissues and/or promoting angiogenesis (c), or display on their surface molecules that direct them to, and cause them to be retained in, damaged tissues (d) (adapted from Ratajczak et al. [16])