Wound Healing Society

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Epithelial Hypoxamir Mir-210 Directly Contributes To Ischemic Skin Injury
Ayan Biswas, Subhadip Ghatak, Mohamed El Masry, Savita Khanna, Sashwati Roy, Chandan K. Sen.
Ohio State University, columbus, OH, USA.

BACKGROUND - Chronic wounds are commonly associated with peripheral vasculopathies. Limitations in the ability of the vasculature to deliver O2-rich blood to the wound tissue leads to, among other consequences, hypoxia. Thus, hypoxia is a subset of ischemia. Hypoxia inducible microRNAs, or hypoxymiRs play a significant role in determining outcomes following ischemic insult. miR-210 is widely regarded as a master hypoxymiR. METHODS - To determine the significance of keratinocyte specific miR-210 during ischemic injury, an animal model with keratinocyte specific knockout of miR-210 (K14cremiR-210Δ/Δ) was developed by crossbreeding mice carrying floxed miR-210 allele (miR-210fl/fl) with tamoxifen inducible K14-Cre mice. A mono-pedicle flap was developed on the back of the mice by making 30-mm-long full-thickness parallel incisions 10 mm apart. Flap edges were cauterized and then sutured to the adjacent skin. Epithelial keratinocytes were collected using Laser Capture Microdissection (LCM) from the skin flap. RESULTS - Significant knockdown (~50%) of miR-210 was noted in the skin epithelium of the K14cremiR-210Δ/Δ mice compared to their wildtype littermates. Using mono-pedicle model of graded ischemia, induction of miR-210 was dependent on the extent of lack of blood flow at d3 post-surgery. The extent of ischemia was categorically characterized by dividing the flap into three parts (proximal, intermediate and distal). The level of ischemia gradually increased from the proximal to the distal part. Similar finding was observed for miR-210 abundance in LCM-captured epithelium pointing towards the involvement of keratinocytes. Interestingly, miR-210 was elevated, potentially contributed by inflammatory cells, in the distal region of the flap in the K14cremiR-210Δ/Δ. Furthermore, K14cremiR-210Δ/Δ mice showed increased perfusion 3 days after mono-pedicle ischemic flap surgery compared to that of the wildtype. Such advantage in blood flow caused flap survival in K14cremiR-210Δ/Δ mice. CONCLUSIONS - Inhibition of keratinocyte specific miR-210 in the ischemia-affected limb is an effective therapy strategy to improve ischemic chronic wound outcomes.


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