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Published on: June 3, 2018
YAP knockdown repressed autophagy in fibroblasts to accelerate wound healing through regulating En1/mTOR axis
1Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo, Japan. kkishi@a7.keio.jp.
Objective:
Wound repair dysfunction is becoming a major public health issue worldwide. Yes-associated protein (YAP) has previously been reported to be closely related to wound healing, while how YAP accelerates wound healing via regulating autophagy needs to be further probed.
Materials And Methods:
ICR male mice were involved in two independent animal experiments; the mice were randomly allocated into control, autophagy inhibitor (3-MA) (injection), and 3-MA (drip) group or control, si-NC, si-YAP group (8 mice for each). Full-thickness excisional wounds (8 mm) in mice were created by punch to construct an in vivo wound model to observe the effects of autophagy inhibitor (3-MA) (by injection and drip) and si-YAP by electrotransfection.
Results:
Firstly, we found that the autophagy inhibitor (3-MA) accelerated wound closure in vivo. Loss-of-function experiments subsequently revealed that YAP knockdown led to increased proliferation and migration of fibroblasts as well as reduced autophagy, resulting in accelerated wound healing. In addition, our results revealed that YAP could positively regulate Engrailed-1 (En1) expression in fibroblasts. En1 knockdown also promoted the proliferation and migration of fibroblasts, meanwhile resulting in increased mammalian target of rapamycin (mTOR) levels and reduced autophagy in fibroblasts.
Conclusions:
YAP knockdown repressed autophagy in fibroblasts to accelerate wound closure by regulating the En1/mTOR axis.
Insights
Yes-associated protein (YAP) knockdown accelerates wound healing by reducing fibroblast autophagy via the Engrailed-1/mammalian target of rapamycin pathway. This finding offers new insights into wound repair mechanisms.
Area of Science:
- Cell Biology
- Wound Healing Research
- Molecular Mechanisms
Background:
- Wound repair dysfunction is a significant global health concern.
- Yes-associated protein (YAP) is implicated in wound healing, but its role in regulating autophagy requires further investigation.
Purpose of the Study:
- To investigate how YAP influences wound healing by modulating autophagy.
- To elucidate the molecular pathways involved in YAP-mediated wound repair.
Main Methods:
- An in vivo mouse model of excisional wounds was established.
- Experiments involved the use of an autophagy inhibitor (3-MA) and YAP knockdown via siRNA electrotransfection.
- Fibroblast proliferation, migration, and autophagy levels were assessed.
Main Results:
- Autophagy inhibition (3-MA) accelerated wound closure in vivo.
- YAP knockdown enhanced fibroblast proliferation and migration while reducing autophagy, leading to faster wound healing.
- YAP positively regulates Engrailed-1 (En1) expression; En1 knockdown mimicked YAP knockdown effects on fibroblasts and autophagy via the mTOR pathway.
Conclusions:
- YAP knockdown accelerates wound closure by repressing autophagy in fibroblasts.
- The En1/mTOR axis is a key mediator in YAP's regulation of fibroblast autophagy and wound healing.
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