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Review
. 2017 Jan 6:57:125-154.
doi: 10.1146/annurev-pharmtox-061616-030146. Epub 2016 Oct 28.

Stem Cell Extracellular Vesicles: Extended Messages of Regeneration

Milad Riazifar  1   2   3   4   5   6 , Egest J Pone  1   2   3   4   5   6 , Jan Lötvall  7   8 , Weian Zhao  1   2   3   4   5   6
Affiliations
Review

Stem Cell Extracellular Vesicles: Extended Messages of Regeneration

Milad Riazifar et al. Annu Rev Pharmacol Toxicol. .

Abstract

Stem cells are critical to maintaining steady-state organ homeostasis and regenerating injured tissues. Recent intriguing reports implicate extracellular vesicles (EVs) as carriers for the distribution of morphogens and growth and differentiation factors from tissue parenchymal cells to stem cells, and conversely, stem cell-derived EVs carrying certain proteins and nucleic acids can support healing of injured tissues. We describe approaches to make use of engineered EVs as technology platforms in therapeutics and diagnostics in the context of stem cells. For some regenerative therapies, natural and engineered EVs from stem cells may be superior to single-molecule drugs, biologics, whole cells, and synthetic liposome or nanoparticle formulations because of the ease of bioengineering with multiple factors while retaining superior biocompatibility and biostability and posing fewer risks for abnormal differentiation or neoplastic transformation. Finally, we provide an overview of current challenges and future directions of EVs as potential therapeutic alternatives to cells for clinical applications.

Keywords: bioengineering; drug delivery; exosomes; extracellular vesicles; microvesicles; stem cells.

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Figures

Figure 1
Figure 1
Biogenesis of extracellular vesicles (EVs). Microvesicles derive from the plasma membrane in a way reminiscent of the reverse of endocytosis. Exosomes are generated as intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs), which, in turn, originate either from invaginations of the plasma membrane or from intracellular organelle membranes. Exosomes are created during two successive membrane invaginations: Membranes invaginate inward to generate MVBs, which in turn invaginate inward to generate ILVs.
Figure 2
Figure 2
Anatomy of EVs. EVs contain several characteristic lipids, proteins, and RNA molecules depicted here schematically. Because exosomes are generated when ILVs are released upon MVB fusion with the plasma membrane, exosomes have the same membrane leaflet composition as ILVs. Surface proteins include MHC molecules, ICAMs, integrins, tetraspanins (e.g., CD63, CD81), TSG101, and ALIX. Lumen proteins include cytoskeletal actin and tubulin, Rab GTPases, and inner membrane leaflet-associated proteins. RNAs include mRNA, lncRNA, miRNA, piRNA, vaultRNA, Y-RNA, rRNA, and tRNA (not all depicted here). During MVB biogenesis and development, ILVs may incorporate additional lipids, proteins, and nucleic acids in a nonspecific bystander way or by specific recruitment. Abbreviations: EV, extracellular vesicle; ICAM, intercellular adhesion molecule; ILV, intraluminal vesicle; lncRNA, long noncoding RNA; MHCI, major histocompatibility complex class I; miRNA, microRNA; mRNA, messenger RNA; MVB, multivesicular body; piRNA, picoRNA; rRNA, ribosomal RNA; tRNA, transfer RNA.
Figure 3
Figure 3
EVs in bidirectional communication between stem and parenchymal cells. Stem cells may sense parenchymal cell injury or distress by receiving parenchymal EVs, and in turn, stem cell EVs harboring prohealing RNAs and proteins may be received by parenchymal cells, maintaining tissue homeostasis. Cellular cytonemes and cilia can establish direct contact between cells for transfer of biomolecules and can also serve as transmission points for EVs. During development, cytonemes and EVs also carry morphogens such as Wnt, Hh, and Notch ligands. Abbreviations: EV, extracellular vesicle; ICAM, intercellular adhesion molecule; MHCI, major histocompatibility complex class I.
Figure 4
Figure 4
Bioengineering EVs for targeted therapy. EVs can be engineered to incorporate nucleic acids and POIs. To concentrate a protein in the lumen of EVs, its interacting partner can be fused with tetraspanin CD63. Likewise, miRNAs can be enriched into EVs by fusing Ago protein with CD63. Poly A binding protein, which binds mature mRNAs, can recruit mRNAs selectively into EVs. lncRNAs can be enriched in EVs by fusing motifs from polycomb repressive complex 2 (EZH1 and EZH2) with tetraspanins. To incorporate POIs on the membranes of EVs, sequences coding for acylation motifs or membrane-spanning helices can be fused to the POIs. Abbreviations: EV, extracellular vesicle; lncRNA, long noncoding RNA; miRNA, microRNA; POI, protein of interest.
Figure 5
Figure 5
Stem cell extracellular vesicles (EVs) for clinical applications. EVs are designed, manufactured, and quality controlled beforehand and stored as off-the-shelf medications to be infused in patients as needed. Other EVs may also be customized accordingly for the individual patient by harvesting autologous stem cells, expanding and modifying them, producing EVs, and infusing them back to the same patient. In this process, the stem cells can also be genetically modified, and their EVs may undergo further modification by loading them with therapeutic molecules. Finally, EVs need to undergo quality control and be stored for future administration.
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