Abstract
Background: Angiogenesis, as an endogenous repair mechanism, plays crucial roles in wound healing and tissue regeneration. However, this process is impaired in the elderly due to aging-related vascular endothelial dysfunction. This study was aimed to explore the pro-angiogenic effects of exosomes from human embryonic stem cells (ESC-Exos) in aged mice of pressure-induced ulcer model and the underlying mechanism. Methods: Pressure ulcer wounds were created on the back of D-galactose-induced aging mice. ESC-Exos were locally applied onto the wound beds once a day, with PBS as control. The effects of ESC-Exos on wound healing were analyzed by measuring wound closure rates, histological and immunofluorescence analyses. Then the anti-aging effect of ESC-Exos on vascular endothelial cells was tested in an in vitro D-galactose-induced HUVEC senescence model. Findings: ESC-Exos could accelerate wound closure and enhance angiogenesis, and the senescence of vascular endothelial cells was significantly ameliorated after ESC-Exos treatment. In vitro, ESC-Exos could rejuvenate the senescence of endothelial cells and recover compromised proliferation, migratory capacity, and tube formation. This recovery was Nrf2-activation-dependent, since cotreatment with Nrf2 inhibitor Brusatol could abolish the rejuvenative effects of ESC-Exos. Further study revealed that miR-200a was highly enriched in ESC-Exos and played a crucial role in ESC-Exos-mediated rejuvenation through downregulating Keap1, which negatively regulates Nrf2 expression. Interpretation: ESC-Exos ameliorate endothelial senescence by activating Nrf2, and recover aging-related angiogenic dysfunction, thereby accelerate wound healing in aged mice. ESC-Exos might be a natural nano-biomaterial for aging-related diseases therapy. Funding: National Natural Science Fund (81472152 and 81572223). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: Animal care and experimental procedures were approved by the Animal Research Committee of the Sixth People’s Hospital at the Shanghai Jiao Tong University.
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