Accelerated Wound Healing by mTOR Activation in Genetically Defined Mouse Models

Abstract

BackgroundThe management of slow or non-healing ulcerations constitutes an increasing clinical challenge in the developed world because of the ageing of the population and the pandemic rise in type II diabetes. Recent studies suggest that molecular circuitries deployed by tumor cells to promote cancerous growth may also contribute to tissue regeneration. Here, we exploited this emerging information to search for novel molecular targets to accelerate wound healing.Methodology/Principal FindingsWe found that the activation of the PI3K-Akt-mTOR pathway, whose aberrant function is a frequent event in human neoplasia, represents an integral component of the normal wound healing process. By the use of genetically defined approaches, including the epithelial-specific ablation of Pten and Tsc1, we show that mTOR activation can dramatically increase epithelial cell proliferation, migration, and cutaneous wound healing, while pharmacological inhibition of mTOR with rapamycin delays wound closure.Conclusions/SignificanceOverall, our findings indicate that the transient pharmacologic activation of the PI3K-Akt-mTOR signaling axis may represent a novel clinical intervention strategy to accelerate the healing of debilitating and life-threatening wounds.

Extracellular Heat Shock Protein 90 Signals through Subdomain II and the NPVY Motif of LRP-1 Receptor to Akt1 and Akt2: a Circuit Essential for Promoting Skin Cell Migration In Vitro and Wound Healing In Vivo

“…These data suggest that different extracellular stimuli require various degrees of threshold Akt kinase activity for signaling. Furthermore, our findings in this study also connect well with those in several recent reports showing that the downstream effect of Akt, the mTOR pathway, plays an essential role in wound healing (33)(34)(35)(36)(37)(38). Therefore, taking all this together, it is becoming clear that the eHsp90␣-subdomain II of LRP-1-NPVY motif-Akt1/2-mTOR pathway represents a new therapeutic target for skin wound healing.…”

Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size

“…Although not well defined functionally at this point, Akt has been shown to be activated and important for wound repair (Squarize et al, 2010). Previously, we have shown that gap-junctional communication within the first 6 hours post wounding is crucial for migration of primary human keratinocytes to fill the wounded region (Richards et al, 2004), so S373 phosphorylation might occur to increase communication in this time frame.…”

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

“…Constitutively active Akt repressed miR-199a-5p expression and was associated with accumulation of miR-199a-5p target HIF-1␣ (8). Given the fact that activation of both HIF (56,57) and Akt (58,59) takes place in the early stage of skin wound healing, it is tempting to speculate that these two pathways might act simultaneously to suppress miR-199a-5p expression, resulting in derepression of Ets-1 and enabling wound angiogenesis in a MMP-1-dependent mechanism. Further investigation is required to characterize the upstream stimuli in regulating the wound-associated down-regulation of miR-199a-5p.…”