Skin ulcers and other forms of non-healing wound are a major problem for the elderly. Chronic inflammation, the presence of senescent cells, decline in stem cell function, and other features of aging conspire to degrade regenerative capacity. First generation stem cell therapies have shown some utility in promoting regeneration in older individuals, but it appears that benefits are near entirely mediated by the signals delivered by transplanted cells in the short period of time before they die. Thus, why not just deliver the signals, and skip the cells? This is an easier task from a logistical point of view.
As it turns out, a sizable fraction of signals carried between cells are transported within extracellular vesicles such as exosomes. These are small membrane-wrapped packages containing a highly varied mix of proteins that is yet to be catalogued in any extensive and reliable way. Harvesting exosomes from a cell culture and then delivering them to a patient is a very viable form of therapy, however, with far fewer attendant challenges than delivering cells. In the past few years, researchers have demonstrated benefits in numerous animal studies.
Today's open access paper is interesting for the effect on senescent cells noted when exosomes are delivered to ulcers in mice. These wounds exhibit significant numbers of senescent cells, and it might be presumed that these cells are disruptive to the healing process. Normally, in young animals, senescent cells are created during the healing process, but are quickly destroyed after delivering pro-growth signals that help to coordinate regeneration. When they linger, however, they instead generate chronic inflammation and interfere in other ways with regenerative processes. After delivery of exosomes, however, there are fewer senescent cells and improved regeneration. Is this reduction in senescent cells because the exosomes cause them to self-destruct, or because they help the immune system to destroy them? That is a question for further research, but it is most interesting to see that we might consider delivery of exosomes from embryonic stem cells to be a senolytic therapy to some degree.
Aging is an inevitable biological process. Senescent cells accumulating in various tissues during aging contribute to organismal aging and disrupt wound healing after injury. Pressure ulcer wounds, particularly for elderly populations, have been reported to heal poorly, because of aging-related changes in skin tissue. Stem cells, holding great therapeutic promise for various aging-related disorders, have been demonstrated to accelerate wound healing in aged mice, though the underlying mechanisms remain unclear. And, whether stem cell-derived exosomes could promote wound healing in aged individuals is barely reported. In this study, exosomes from human embryonic stem cells (ESC-Exos) were locally applied to treat pressure ulcer wounds in an aged mice model induced by D-gal treatment. We found that chronic ESC-Exos treatment effectively rejuvenate endothelial cell senescence and promote angiogenesis, enhancing wound healing.
Angiogenesis, the process by which new blood vessels are formed, plays vital roles in wound healing. We have previously reported that the underlying mechanisms of tissue recovery after exosome treatment partly involve exosome-mediated pro-angiogenesis effects, including cutaneous wound healing, ischemic hindlimb injury repair, and bone regeneration. Vascular endothelial cells are major effector cells in the angiogenic process of pressure ulcer healing; aging-related endothelial dysfunction and impaired angiogenesis likely contribute to delayed wound healing in the elderly. And applying anti-aging agents to wound beds could rejuvenate cutaneous cell viability, promote neo-vascularization, and enhance wound healing in aged skin. Thus, rejuvenating endothelial senescent cells and reversing aging-associated angiogenic dysfunction seem to comprise a promising therapeutic approach for wound healing in aged individuals.
In our study, we found that the number of senescent endothelial cells at wound beds was significantly reduced after chronic application of ESC-Exos. Also, D-gal-induced senescence in HUVECs was used to evaluate the rejuvenative effects of ESC-Exos in vitro; we found that endothelial senescence is correlated with a decrease in endothelial function (e.g., proliferative, migrative, and tube formation capacities), which is in accordance with the results of previous research. Moreover, chronic ESC-Exos treatment could reduce the aging hallmarks and recover the compromised function. Thus, the therapeutic effects of ESC-Exos on pressure ulcer healing in aged skin may be mainly attributed to their function in rejuvenating endothelial senescent cells and recovering angiogenic function.