Abstract
BackgroundAngiogenesis, 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.MethodsPressure ulcer wounds were created on the back of d-galactose-induced aging mice. ESC-Exos were locally applied onto the wound beds, 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.ResultsESC-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.ConclusionsESC-Exos ameliorate endothelial senescence by activating Nrf2 and recover aging-related angiogenic dysfunction, thereby accelerating wound healing in aged mice. ESC-Exos might be a natural nano-biomaterial for aging-related diseases therapy.
Highlights
Angiogenesis, as an endogenous repair mechanism, plays crucial roles in wound healing and tissue regeneration
By Western blot analysis, we demonstrated the presence of exosomal markers, including CD9, CD63, and TSG101, but not of the cis-Golgi matrix protein GM130, Actin, and Lamin A/C (Fig. 1f ), which means no contamination of cellular components in isolated exosomes
In summary, we for the first time demonstrate that the embryonic stem cells (ESCs)-Exos accelerate wound healing process and promote local angiogenesis at wound site in aged mice by rejuvenating endothelial senescence
Summary
Angiogenesis, as an endogenous repair mechanism, plays crucial roles in wound healing and tissue regeneration. 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. Successful treatment of aging-associated diseases could benefit from stem cell-based therapy, which could regenerate functional integrity and contribute to tissue homeostasis [8]. Accumulating studies have revealed that exosomes possess parental stem cell-like pro-regenerative effects against multiple diseases in animal models [15, 16], with no risk of aneuploidy and a lower possibility of immune rejection [17]. Since qualified ESC-Exos can be obtained infinitely from ESCs, and is convenient for industrial production, it holds great potential in anti-aging therapy
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