Abstract
Secretomes from various cell sources exert strong regenerative activities on numerous organs, including the skin. Although secretomes consist of many diverse components, a growing body of evidence suggests that small extracellular vesicles (EVs) account for their regenerative capacity. We previously demonstrated that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCs) exhibits wound healing capacity. Therefore, we sought to dissect the molecular composition of EVs present in the secretome and compared wound healing-related activities of these EVs to other subfractions of the secretome and the fully supplemented secretome (MNCaposec). Compared to EVs derived from non-irradiated PBMCs, γ-irradiation significantly increased the size and number and changed the composition of released EVs. Detailed characterization of the molecular components of EVs, i.e. miRNA, proteins, and lipids, derived from irradiated PBMCs revealed a strong association with regenerative processes. Reporter gene assays and aortic ring sprouting assays revealed diminished activity of the subfractions compared to MNCaposec. In addition, we showed that MNCaposec accelerated wound closure in a diabetic mouse model. Taken together, our results suggest that secretome-based wound healing represents a promising new therapeutic avenue, and strongly recommend using the complete secretome instead of purified subfractions, such as EVs, to exploit its full regenerative capacity.
Highlights
Secretomes from various cell sources exert strong regenerative activities on numerous organs, including the skin
As the availability and accessibility of stem cells of different origins are limited and it is time-consuming and extremely expensive to produce them under Good Manufacturing Practice (GMP) conditions[20], we focused on peripheral blood mononuclear cells (PBMCs) as a source for secretome production
We have shown that the secretome of γ-irradiated PBMCs (MNCaposec) has regenerative capacity in several preclinical settings
Summary
Secretomes from various cell sources exert strong regenerative activities on numerous organs, including the skin. Many organs have demonstrated morphological plasticity and the capacity for healing instead of being post-mitotic terminally differentiated in preclinical and clinical trials of regenerative medicine utilizing stem cells[1,2,3,4]. Transplantation of adult stem cells has been proposed and tested to repair different kinds of tissue damage The rationale for such an approach was derived from studies demonstrating the capacity of bone marrow-derived cells to transdifferentiate into various cells types, including neurons, cardiomyocytes, hepatocytes, bone and skin cells, just to name some[5,6]. Small EVs derived from stem cells or platelet-rich plasma were shown to significantly contribute to wound healing processes in different rodent models[18,19]
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