Extracellular vesicles: potential roles in regenerative medicine

Abstract

Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell-cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering.

Keywords: exosomes; extracellular vesicles; microvesicles; regenerative medicine; tissue engineering.

Figure 1

Bio-activated artificial scaffolds. Electrospinning allows formation of constructs with a variety in shapes, sizes, and tissue strength. This allows the production of constructs for a variety of tissues (left). Electrospun fibers (middle) can be bio-activated by coating of the fibers with proteins or peptides (right, red). Incorporation of bio-active components into the fibers will result in gradual release during fiber degradation (right, green). After electrospinning, fibers can also be pre-seeded with appropriate cell populations to induce ECM production, angiogenesis, or immunomodulation (right, yellow).

Figure 2

EV formation (left) and intercellular communication (right). After endocytosis, intraluminal vesicle formation occurs in the late endosome, resulting in the formation of the multivesicular body (MVB). The MVB can either fuse with the lysosome, resulting in breakdown and recycling of its contents, or fuse with the plasma membrane, resulting in the release of the intraluminal vesicles, which are then deemed exosomes. Microvesicles shed directly from the plasma membrane. Intercellular communication can occur through three major processes: (1) direct interaction of ligands expressed on the surface of EV with receptors on the cell membrane, (2) direct fusion of the EV with the cell membrane, resulting in the release of the content of the EV, or (3) internalization through the endocytotic pathway, which can result in (A) fusion of the EV with membrane of the endosome, resulting in content release, (B) transcytosis, or (C) degradation through the lysosomal pathway.

Figure 3

Applications of EV in regenerative medicine. After isolation (A), EV could be utilized in regenerative medicine through a number of methods, either separately or in combination with cells or other therapeutics. (B) Direct injection into tissue or circulation. (C) Mixing of EV in hydrogels. (D) Coating electrospun fibers indirectly via chemical linkers, antibodies, or specific tags engineered on to the EV. (E) Coating of electrospun fibers with bio-degradable gels such as fibrin, resulting in gradual release during gel degradation.