To what degree can skin be restored to a more youthful state just by changing cell behavior? That question will be explored comprehensively in the years ahead, and not just for skin. Many research groups are taking the approach of harvesting extracellular vesicles from stem cells and delivering them into tissues, a potential form of therapy that appears to produce many of the same benefits as first generation stem cell transplants, and with less expense and complexity.
What fraction of these benefits are a matter of overriding unfortunate cellular reactions to damage, or putting damaged cells back to work, hopefully without reaching the threshold at which this would produce an increased cancer risk? How much is a genuine clean-up of metabolic waste or damaged components in cells? That remains to be determined, but it is worth bearing in mind that there are forms of metabolic waste and cell damage that our biochemistry cannot deal with, no matter how fired up it might be. Ultimately, the research community must do better than simply instructing our cells to work harder. Tools must be provided to break down that waste, irreparably damaged stem cells replaced, and more.
Stem cells have attracted great interest from the scientific community since their discovery. Their capacity to differentiate into various cell types and hence provide tissue repair made them promising tools in the treatment of such pathologies as neurodegenerative disorders, organ failure, and tissue damage. However, stem cells such as mesenchymal stem/stromal cells (MSCs) exert their functions via paracrine effects and not by the replacement of dead cells.
The term secretome refers to the complex mixture of factors released by virtually all cell types, including stem cells, to the extracellular space. Once released by stem cells, this combination of different classes of molecules can modify microenvironments by controlling inflammation as well as inducing selective protein activation and transcription. This secreted milieu of molecules may culminate in tissue regeneration. Recent evidence about this paracrine mechanism has opened up a new paradigm in stem cell therapy and stimulated the search for strategies that explore the concept of "cell therapy without cells."
The most well-studied and dynamic part of the growing field of secretomics is extracellular vesicles (EVs). EVs represent an important fraction of virtually any cell type's secretome. Extensive research is currently being conducted to elucidate the healing potential of stem cell EVs in numerous disease processes. EVs released by stem cells to the extracellular space have been shown to improve vascularization, immunomodulation, and cardiac and central nervous system regeneration.
Stem cell-conditioned media from endothelial precursor cells differentiated from human embryonic stem cells have been used in skin rejuvenating research with interesting results. The injection of conditioned media from those cells improved the aspect of skin wrinkles and skin aspect in women. UV light damage and aging affect extracellular matrix collagen and elastin depots, both of which are key in the prevention of skin dehydration as well as in firmness and elasticity preservation. The beneficial effects of stem cell EVs for cellular matrix maintenance and collagen production as described previously could contribute to this effect, considering that vesicles are important components of stem cell-conditioned media.
Furthermore, reports have suggested that purified stem cell EVs could play a role in rejuvenating skin cells. A report indicated that EVs from induced pluripotent stem cells (iPSCs) could restore the function of aged human dermal fibroblasts. The authors reported that dermal fibroblasts pretreated with iPSC EVs resisted photoaging with UVB and did not overexpress matrix-degrading enzymes MMP-1/3 but, on the contrary, displayed a high expression of collagen I, as young fibroblasts do. Other researchers studied the capacity of human umbilical cord stem cell EVs to rejuvenate skin by modulating collagen production and permeation. They also investigated whether EVs acceptance could accelerate fibroblast proliferation. Not only did skin cells proliferate more after EVs endocytosis, but a better production of collagen and elastin in human skin models was also observed in their study. Altogether, these studies indicate that stem cell EVs could be good candidates for therapeutic strategies against aging.