The role of microvesicles in tissue repair

Abstract

Microvesicles (MVs) are released by almost all cells in resting and activated conditions. First described several years ago, it is only recently that their mechanisms of action are being elucidated, and their potential role in health and disease is drawing increasing attention. The main function of MVs is signaling through specific interactions with target cells and the transferring of gene products. Gaining further insights into the molecular specificity of MVs has allowed identification of the cellular source and may provide new diagnostic tools in the future. Indeed, an increasing body of evidence indicates that MVs are capable of mediating tissue repair in models of acute kidney and liver injury. In this review, we will discuss the mechanisms through which MVs from stem cells may act on target cells and may modify the response to injury. Furthermore, MVs from inflammatory cells are suspected to be involved in various diseases, such as cardiovascular and renal diseases, pathological pregnancy, tumors and sepsis. MVs are no doubt also involved in modulating immunity, and future studies will clarify their functional role in negatively modulating the cell response. Their role in physiological and pathological processes is increasingly appreciated. Depending on the cell source and the condition, MVs may be either beneficial or detrimental to the host. The recognition of their pathogenetic role may suggest new approaches to future therapies.

Figure 1

Effects of i.v. injection of MVs from human MSCs in rats with AKI induced by ischemia-reperfusion and in mice with AKI induced by glycerol injection, treated or not with MVs derived from human MSCs. Representative micrographs of renal histology (Haematoxylin and Eosin staining) at day 2 after IRI of rats treated or not with 30 µg of MVs and at day 4 after glycerol injection of mice treated or not with 15 µg of MVs. Original magnification: x400. (described in ref. 32).

Figure 2

Renal cell proliferation and apoptosis in rats with AKI induced by ischemia-reperfusion and in mice with AKI induced by glycerol injection, untreated or treated with MVs derived from human MSCs. (A) Representative micrographs of PCNA staining and TUNEL assays performed on sections of kidneys 2 days after IRI, treated or not with 30 µg of MVs. Magnification: x400. (B) Representative micrographs of PCNA staining performed on sections of kidneys 4 days after glycerol injection, treated or not with 15 µg of MVs. Magnification: x400. (Described in ref. 14).

Figure 3

Proliferative effect of HLSC-derived MVs in experimental 70% hepatectomy. Effect of MVs on liver cell proliferation evaluated as BrdU (A and B) and as PCNA (C and D) incorporation in 70% hepatectomized rats. (A and B) Representative micrographs of BrdU uptake performed on sections of liver 24 hrs after 70% hepatectomy in rats treated with vehicle (A) or treated with 30 g MVs (B). BrdU was injected intraperitoneally 2 hrs before rats were killed. Original magnification: x200. (C and D) Representative micrographs of PCNA staining performed on sections of liver 24 hrs after 70% hepatectomy in rats treated with vehicle (C) or treated with 30 g MVs (D). Original magnification: x200. (Described in ref. 54).

Figure 4

Rotary bioartificial liver device. (A) Photograph of the bioarticificial liver used in the experiments described in reference . (1) Gas supply: O₂, N₂, CO₂ and pressure air, connected to flowmeter. (2) Pump, regulates media-circulation. (3) Heating device with power supply. (4) Tube system containing bubble traps to avoid air bubbles entering in the circuit. (5) Oxygenator mediates gas flux to media circuit. (6) Chamber containing cells fixed into the reactor's rotation unit. (7) Reactor, housing for chamber and central unit of the rotary bioartificial liver provided by Fresenius Medical Care in cooperation with the University of Innsbruck, Austria. (B) HLSCs are placed in the dialysate compartment followed by their proliferation and aggregate formation around the hollow fibers (insert). HLSCs produce high concentratons of growth factors (e.g., HGF) that are reinfused into the venous line. This makes the rotary bioartificial liver device a source of conditioned media capable of exerting important, hepatotropic effects, such as induction of proliferation and inhibition of apoptosis.