Clinical applications of exosome membrane proteins

Abstract

Extracellular vesicles (EVs) are small membranous particles that can mediate cell-to-cell communication and which are divided into at least three categories according to their subcellular origin and size: exosomes, microvesicles, and apoptotic bodies. Exosomes are the smallest (30-150 nm) of these EVs, and play an important role in EV-mediated cell-to-cell interactions, by transferring proteins, nucleic acids and, lipids from their parental cells to adjacent or distant cells to alter their phenotypes. Most exosome studies in the past two decades have focused on their nucleic acid composition and their transfer of mRNAs and microRNAs to neighboring cells. However, exosomes also carry specific membrane proteins that can identify the physiological and pathological states of their parental cells or indicate their preferential target cells or tissues. Exosome membrane protein expression can also be directly employed or modified to allow exosomes to serve as drug delivery systems and therapeutic platforms, including in targeted therapy approaches. This review will briefly summarize information on exosome membrane proteins components and their role in exosome-cell interactions, including proteins associated with specific cell-interactions and diseases, and the potential for using exosome membrane proteins in therapeutic targeting approaches.

Keywords: Exosome; diagnostic markers; endocytosis; exosome mimetics; membrane fusion; membrane protein; target therapy.

Figure 1

Mechanism of EV to cell interactions. Exosome uptake appears primarily mediated by (a) the standard phagocytosis machinery in professional phagocytes, and (b) receptor-mediated endocytosis in other cell types (e.g. CD29/CD81- or fibronectin-mediated interactions). However, exosomes also exhibit (c) paracrine signaling, where factors released by exosomes can directly adhere to cell surface receptors, and (d) receptor-mediated membrane fusion via interactions between exosome and cell membrane proteins (e.g. syncytins and MFSD2a or ASCF2).

Figure 2

The special functions of some exosome membrane proteins. 1) Immune cell activation (e.g. antigen-presenting cells secrete exosomes that carry MHC II-antigen complexes that can stimulate T-cell responses); 2) Cell-specific markers (e.g. the transmembrane protein ASGR can serve as a specific marker for exosomes derived from hepatocytes); 3) Metastatic potential (e.g. exosomes expressing E-cadherin which can promote ovarian cancer metastasis); 4) Exosome homing (e.g. integrins on cancer-derived exosomes can predict organs at a risk for future metastasis); 5) Immune cell repression (e.g. exosome PD-L1 expression can indirectly inhibit immune responses).

Figure 3

Exosome membrane protein therapy. Several approaches have been taken to develop exosome-based or exosome mimetic therapeutics. These include: (a) non-modified exosome therapeutics, employing native exosome surface proteins (SCAMP, HSP70, CD9) to recognize specific proteins to carry out specific tissue-directed functions; (b) non-recombinant exosome modifications; (c) recombinant exosome modifications; and (d) membrane-coated exosome mimetics.