The emerging role of microvesicles in cellular therapies for organ/tissue regeneration

The field of regenerative medicine is searching for a source of stem and progenitor cells that can be safely and efficiently employed for regeneration of damaged organs (e.g. heart, liver or kidney) [1–3]. In experimental animal models of organ damage (e.g. heart infarct), different types of stem cells isolated from adult tissues have been employed, including bone marrow-derived mononuclear cells, hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), skeletal muscle myoblasts and so-called cardiac stem cells (CSCs). Interestingly, while some beneficial effects have been reported using cellular therapies, there is no solid evidence that cells employed to regenerate damaged tissues truly give rise to organ-specific cell populations (e.g. functional cardiomyocytes in heart, hepatocytes in liver or tubular epithelium in kidney). Furthermore, much of the previously published data purporting to show transdifferentiation of transplanted cells into cells that comprise damaged organs has been subsequently explained by a rare cell fusion phenomenon [4]. As a result of fusing transplanted cells with cells residing in the damaged tissues, new cells with double the number of chromosomes (heterokaryons) are created. Such heterokaryons may express somemarkers of the transplanted cells employed for therapy and thus may give the false impression that the transplanted cells have replaced the damaged ones. This phenomenon, however, is extremely rare and it is nowwidely accepted that it was unduly emphasized in the past as a major mechanism contributing to tissue and organ chimerism following cellular therapy [4,5]. The issue remains that in all of the tissue-damage models reported so far, no solid evidence has been presented that transplanted cells truly trans-differentiate into cell populations specific to the injured organ. Moreover, since similar beneficial effects in improvement of organ function (e.g. for the left ventricular ejection faction) after cell therapy were often observed regardless of which cells were employed, it became obvious that some other cell-mediated effects must be responsible for the observed effects that ameliorate organ damage [6,7]. To begin with, those effects might be explained by paracrine signals from the transplanted cells. In fact, it is very well known that MSCs, and even highly purified HSCs, secrete several growth factors, cytokines or chemokines that prevent apoptosis of cells residing in damaged tissues [8]. In addition, some of the secreted factors could also stimulate angiogenesis and thus, by improving local circulation, improve the function of damaged tissues. However, on the assumption that every cell type possesses a unique repertoire of secreted factors, other common cell-dependent mechanisms may play an important role as well. The paper published by Dr Camussi’s group in this issue of Nephrology Dialysis and Transplantation provides elegant evidence that some crucial protective and pro-regenerative mechanisms are mediated by cell-derived microvesicles (MVs) [9]. These small, circular membrane structures (100 nM–1 μm in diameter) are also referred to as ‘microparticles’ or ‘exosomes’ in the literature [10–12]. Furthermore, MVs secreted in the developing embryo are potential vehicles for the spread of morphogens through epithelia (e.g. Hedgehog proteins) and are known as argosomes [13]. For simplicity, we will use the traditional name (MVs) in this editorial. Overall, MVs, as small circular membrane fragments, are shed from the cell surface or released from the endosomal cell membrane compartment and play an important and underappreciated role in cell-cell communication [10– 12]. This intriguing MV-mediated cell–cell communication system emerged very early during evolution and served as a template for the further development of intercellular interaction mechanisms involving soluble bioactive mediators and fine-tuned ligand–receptor interactions. The first unicellular organisms communicated with each other by sending and receiving MVs. In bacteria, for example, MVs may transfer antiobiotic resistance genes. On the other hand, in amoeba MVs play an important role in marking trails for migrating cells: MV trails left by migrating amoebae provide guidance for other cells that follow ‘in their footsteps’. Furthermore, as mentioned above, in tissues of the develop-