The Potential Role of Microvesicles in Mesenchymal Stem Cell-Based Therapy

Abstract

As plasma membrane-derived particles for intercellular communication, microvesicles (MVs) released from various cell types have increasingly become a focus of interest in stem cell-based therapy. MVs can be harvested by ultracentrifugation at 100,000 g from the supernatants of cells and have a diameter of 100–1000 nm [1,2]. They originate from multivesicular bodies and comprise of 2 regions: the membrane and the internal cargo. The membrane (consisting of proteins and lipids) packages the bioactive molecules, such as lipids, proteins, DNA, mRNA, and micro-RNA [2,3]. The components of MVs are dependent on the parental cells from which they originate and on the mechanisms by which they released them; thus, the function of MVs from different cells may vary. For instance, MVs from tumor cells regulated extracellular matrix degradation, whereas those from endothelial progenitor cells activated the angiogenesis [4,5]. The cargo inside the MVs determines the function after targeting the neighboring cells and the remote ones by fusion or interaction [2,3]. Therefore, the striking effect of MVs on cell-to-cell interaction and tissue regeneration cannot be ignored. Currently, MVs have been isolated from different cells [4– 6], as well as from mesenchymal stem cells (MSCs) [7–9]. MSCs, which have been obtained from a variety of tissues, have been extensively investigated for regenerative strategies, and those from bone marrow (BM-MSCs) are the most widely studied [10–14]. The regenerative mechanisms ascribed to MSCs can be classified into 3 categories: differentiating toward reparative or replacement cell types, enhancing the nutrient supply, and improving the survival and function of the endogenous cells via paracrine actions [15–17]. Because of the inhospitable microenvironment of the injured or degenerating tissues, a large proportion of the implanted MSCs may die or undergo apoptosis in a short period post-transplantation [18,19]. Only a rare proportion of transplanted MSCs remained therefore alive, and evidence of their differentiation in vivo toward mature phenotypes of resident cells is very scanty [18], suggesting that mechanisms other than differentiation of transplanted cells replacing endogenous damaged cells are invoked. Therefore, it was suggested that the paracrine signaling partly evoked the repair [17]. This notion was further supported by experimentation where the MSC-conditioned medium rather than cells themselves and therefore the secreted products of the cells acted as paracrine modulators of tissue regeneration [20–22]. Definitely, most of these secreted molecules from MSCs included cytokines, growth factors, and nucleic acids that cannot span the membranes freely and a vehicle should be involved to facilitate the crossing. Although the underlying mechanisms of transport are not well elucidated, MSCderived MVs have been supposed as shuttles for the functional components for MSC paracrine action. The following 2 reasons would provide a better interpretation. First, MVs are secreted to the extracellular space throughout budding and fission of the membrane [2,7]; thus, they possessed several characteristics of the parental MSCs. For example, MVs isolated from human BM-MSCs were positive for CD29, CD44, and CD73 [23]. In addition, MVs can be labeled by the commonly used fluorescent dyes such as PKH26, so that it is possible to observe the membrane fusion of MVs with the recipient cells in which the phenotypes may change accordingly [23]. These structural patterns are similar with that of MSCs. On the other hand, the containing cargo exerts function similar to those of MSCs. It has been found that human BMMSC-derived MVs were enriched of mature micro-RNA that may be transferred to the recipient cells; in other words, MVs may have a functional impact on the target cells through micro-RNA delivery [24]. Additionally, the transfer of membrane-related proteins and the modulation of immune responses by MSC-derived MVs were recorded [25,26]. Interestingly, the targeted cells would regulate MSCs in the same way that could be determined by the bidirectional intercellular MV transfer between MSCs and nucleus pulposus cells during direct coculture [27]. The above evidence further broadened our current understanding regarding the mechanisms of MSC paracrine actions. Furthermore, like MSCs, MVs demonstrated therapeutic potency. Bruno and colleagues reported that human BM-MSC-derived MVs enhance the proliferation of tubular epithelial cells and protect them from apoptosis induced by serum deprivation, vincristine, and cis-platinum; in vivo studies suggested that MVs could accelerate the recovery from acute kidney injury