Mesenchymal stem cell therapies vary widely in their ability to influence regeneration, though they fairly reliably reduce chronic inflammation in older patients. One challenge is that there is no standard on what constitutes a mesenchymal stem cell; it is a category so broad as to be almost meaningless. Further, two clinics performing what is ostensibly the same protocol using cells from the same source can produce widely divergent outcomes. In most cases, near all transplanted cells die, and the benefits obtained for the patient derive from signaling produced by the stem cells in the short period of survival following transplantation. A large fraction of this signaling is carried by extracellular vesicles, and since these vesicles can be harvested and used for therapy more readily than is the case for cells, many researchers and clinicians are turning their focus towards vesicle-based treatments.

Surprisingly, patients inoculated with mesenchymal stem cells (MSCs) to promote tissue regeneration showed less than 1% of such cells in the damaged tissue after 1 week. Yet, paradoxically, such strategy has produced positive results in the treatment of several pathologies, favoring tissue regeneration and functionality. Therefore, it has been suggested that the regenerative effect of the MSC is not mainly due to their capacity to proliferate and differentiate into the required cellular types in the damaged tissue. Instead, their main functionality would stem from their paracrine actions, through the production of different factors.

Interestingly, such hypothesis is supported by several studies, demonstrating that conditioned media from MSC cultures have a similar regenerative capacity - or even higher - than the MSC themselves. For instance, that has been demonstrated in rodent models of acute myocardial infarction. These results demonstrate the surprising therapeutic relevance of the MSC secretome. In view of these results, it has been proposed to rename such stem cells as "medicinal signaling cells."

The secretome of the MSC has one free fraction, made of soluble factors and metabolites, as well as other encapsulated into microvesicles (MV), to which the extracellular vesicles (EV) belong. Interestingly, it has been found that the latter is the main responsible for the therapeutic properties of the conditioned media from MSC cultures. This way, those EV can regulate different physiological processes, like cellular proliferation, differentiation, and migration. The therapeutic features of the MSC EV are mainly due to their immunomodulatory and immunosuppressive activities.

The use of EVs in therapy has relevant advantages, in relation to MSCs. Among them are the following: (i) can be isolated and stored at low temperatures, until needed, without requiring the production of large amounts of cells at the time of inoculation, which is needed for cellular therapy; (ii) their contents are encapsulated and protected from degradation in vivo (preventing some of the problems associated with small soluble molecules, such as cytokines, growth factors, transcription factors, and RNA, which are rapidly degraded); (iii) are quite stable, exhibiting a long average life; (iv) can be intravenously injected, reaching distant places, since the vesicles are small and circulate readily, whereas the MSC are too large, and thus may have difficulty circulating through thin capillaries; (v) can pass through the blood-brain barrier; and (vi) have reduced risks of unwanted side-effects, such as immune rejection.