Extracellular Vesicles: Evolving Factors in Stem Cell Biology

Abstract

Stem cells are proposed to continuously secrete trophic factors that potentially serve as mediators of autocrine and paracrine activities, associated with reprogramming of the tumor microenvironment, tissue regeneration, and repair. Hitherto, significant efforts have been made to understand the level of underlying paracrine activities influenced by stem cell secreted trophic factors, as little is known about these interactions. Recent findings, however, elucidate this role by reporting the effects of stem cell derived extracellular vesicles (EVs) that mimic the phenotypes of the cells from which they originate. Exchange of genetic information utilizing persistent bidirectional communication mediated by stem cell-EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations. This review therefore discusses stem cell-EVs as evolving communication factors in stem cell biology, focusing on how they regulate cell fates by inducing persistent and prolonged genetic reprogramming of resident cells in a paracrine fashion. In addition, we address the role of stem cell-secreted vesicles in shaping the tumor microenvironment and immunomodulation and in their ability to stimulate endogenous repair processes during tissue damage. Collectively, these functions ensure an enormous potential for future therapies.

Figure 1

The role played by stem cell-derived EVs in the determination of cell fate. Stem cells use EVs to transfer miRNAs and stem cell effectors in recipient cells, which target the regulatory networks and induce persistent genetic transformation and phenotypic switching of resident cells towards cell-fate determination.

Figure 2

Contribution of stem cell-derived EVs in the construction of the tumor microenvironment. Stem cell-derived EVs influence the presence of cancer-associated fibroblasts (CAFs), inflammatory immune cells, metalloproteinases, angiogenic growth factors, and regulatory RNAs, which shape the tumor microenvironment. Extracellular matrix (ECM) remodeling, endothelial cell growth, cell migration, and angiogenesis generate a permissive tumor niche.

Figure 3

Schematic representation of the regenerative effects of stem cell-derived EVs. MSCs use EVs to ameliorate tissue damage through translocating growth factors, anti-inflammatory, antiapoptotic, and proangiogenic molecules, to sites of injury where they induce and regulate regenerative phenotypes.