Microvesicles as mediators of tissue regeneration

Abstract

The use of stem cells in the treatment of various diseases and injuries has received increasing interest during the past decade. Injected stem cells, such as mesenchymal stem cells, stimulate tissue repair largely through the secretion of soluble factors that regulate various processes of tissue regeneration, including inflammatory responses, apoptosis, host cell proliferation, and angiogenesis. Recently, it has become apparent that stem cells also use membranous small vesicles, collectively called microvesicles, to repair damaged tissues. Microvesicles are released by many types of cells and exist in almost all types of body fluids. They serve as a vehicle to transfer protein, messenger RNA, and micro RNA to distant cells, altering the gene expression, proliferation, and differentiation of the recipient cells. Although animal models and in vitro studies have suggested promising applications for microvesicles-based regeneration therapy, its effectiveness and feasibility in clinical medicine remain to be established. Further studies of the basic mechanisms responsible for microvesicle-mediated tissue regeneration could lead to novel approaches in regenerative medicine.

Figure 1. Synthesis and release of microvesicles

(A) Synthesis of exosomes during the process of endocytosis. Exosomes arise from early endosomes through the invagination of the endosomal membrane to form intraluminal vesicles within multivesicular bodies. The intraluminal vesicles are then released as exosomes. (B) Synthesis of microparticles independently of endocytosis. Increases in intracellular Ca²⁺ activate key enzymes, leading to the dynamic redistribution of phospholipids and membrane budding.

Figure 2. Examples of microvesicle-mediated transfer of protein and RNA

(A) FasL on microvesicles from tumor cells binds to Fas on T cells, causing T cell apoptosis and resulting in tumor progression. (B) Transfer of the oncogenic receptor EGFRvIII into glioblastoma cells causes more aggressive growth of the cells. (C) Activated T cells transfer miRNAs into antigen-presenting B cells, modulating their immune response.

Figure 3. Kidney regeneration by the microvesicles released by mesenchymal stem cells and endothelial progenitor cells

(A) Microvesicles derived from mesenchymal stem cells (MSCs) inhibit apoptosis and stimulate proliferation of renal tubular epithelial cells. Microarray analysis of microvesicle RNA detected 239 mRNA species, including species with the functions described at the right. (B) Microvesicles released from endothelial progenitor cells (EPCs) induce quiescent endothelial cells to reenter the cell cycle and form blood vessels. In addition to mRNA species, miRNAs are also transferred by the microvesicles.

Figure 4. Potential dedifferentiation induced by microvesicles derived from embryonic stem cells

Embryonic stem cell (ESC)-specific components of microvesicles, including the abundant miR-290 cluster, potentially affect the cell cycle regulation of fibroblasts and induce dedifferentiation of Müller glia cells.