Abstract
Keratinocyte migration, the initial event and rate-limiting step in wound healing, plays a vital role in restoration of the intact skin barrier, also known as re-epithelialization. After acute tissue injury, hypoxic microenvironment gradually develops and acts as an early stimulus to initiate the healing process. Although we have previously found that hypoxia induces keratinocyte migration, the underlying mechanism remains unknown. Here, we first observed that hypoxia increased mTORC1 activity. Recombinant lentivirus vector and Rapamycin were used for silencing mTORC1 in HaCaT cells and primary mouse keratinocytes (MKs). Using cell migration assay and a Zeiss chamber equipped with imaging system, we also demonstrated that mTORC1 downregulation reversed hypoxia-induced keratinocyte motility and lateral migration. Importantly, hypoxia-activated mTORC1 was accompanied by the AMPK downregulation, and we found that the AMPK pathway activators Metformin (Met) and 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) decreased the mTORC1 activity, cell motility and lateral migration. Thus, our results suggest that hypoxia regulates mTORC1-mediated keratinocyte motility and migration via the AMPK pathway.
Highlights
Wound healing is a dynamic and well-ordered biological process that requires the spatial and temporal orchestration of several distinct components, including coagulation, inflammation, re-epithelialization, contraction and remodeling [1]
We investigated the mechanisms responsible for the augmented motility and migration of keratinocytes in the mild hypoxic microenvironment and found that mTORC1 activation, which was mediated by AMPK suppression, played a vital role in hypoxia-induced cell migration
We demonstrated that hypoxia-induced mTORC1 activation was greatly involved in keratinocytes motility and migration
Summary
Wound healing is a dynamic and well-ordered biological process that requires the spatial and temporal orchestration of several distinct components, including coagulation, inflammation, re-epithelialization, contraction and remodeling [1]. The essential feature of successful wound healing is the reestablishment of the intact epidermal barrier. The term “reepithelialization” refers to an intricate process that the keratinocytes migrate from wound margins to resurface the wounded area. During this process, keratinocyte migration into the wound is the initial event and rate-limiting step [2], since defects in migration, but not in differentiation or proliferation, are closely related with the non-healing wounds. A complex balance of genes and signals are regulated in a temporal and spatial manner to promote
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