Liver is a primary source of insulin-like growth factor-1 in skin wound healing

Abstract

Insulin-like growth factor (IGF)-1 plays important role in tissue repair through its ability to stimulate wound cell activity. While IGF-1 is expressed locally by wound cells, liver-derived IGF-1 is also present at high levels in the circulation, and the contributions of local vs circulating IGF-1 to wound levels remain undefined. The hypothesis of this study was that liver is a primary source of IGF-1 during skin wound healing. To test this hypothesis, we utilized a model that allows inducible ablation of IGF-1 specifically in liver of adult mice. We demonstrate that ablation of liver IGF-1 leads to >85% loss of circulating IGF-1 and ~60% decrease in wound IGF-1 during the proliferative phase of healing in both male and female mice. This reduction of liver-derived IGF-1 did not alter local mRNA expression of Igf1 in wounds. Knockdown of liver IGF-1 significantly delayed wound re-epithelialization and reduced granulation tissue formation and collagen deposition. Knockdown of liver IGF-1 also significantly reduced angiogenesis and resulted in persistent macrophage accumulation. In summary, liver is a primary source of IGF-1 in skin wounds and contributes to many aspects of both epithelial and dermal healing.

Liver insulin‐like growth factor‐1 mediates effects of low‐intensity vibration on wound healing in diabetic mice

“…AAV-Cre or AAV-Null was injected 7 days prior to wounding. AAV8-pTBG-Cre-mediated recombination has proven to be highly specific for hepatocytes and induces greater than 90% reduction in the expression of the floxed allele for up to 8 months [25,[29][30][31].…”

“…The mice were subjected to excisional wounding as described previously [10,11,25]. In brief, the mice were anesthetized with isoflurane, and their dorsum was shaved and cleaned with alcohol.…”

“…Re-epithelialization and granulation tissue thickness were measured in cryosections taken from the center of the wound (found by serial sectioning through the entire wound) and stained with hematoxylin and eosin [19,25,32]. Digital images were obtained using a Keyence BZ-X710 All-in-One Fluorescence Microscope (Keyence, Itasca, IL, USA) with a 2Â or 20Â objective and analyzed using ImageJ software.…”

“…Importantly, IGF1 is present at high levels in the circulation, and the liver is the major source of circulating IGF1 in mice [24]. We recently reported that the liver is a primary source of IGF1 in skin wounds of lean, healthy mice and contributes to angiogenesis, granulation tissue formation, and re-epithelialization [25]. In humans, IGF1 levels in wounds are correlated with those in blood, suggesting that blood is the primary source of wound IGF1 [26].…”

“…To determine whether liver IGF1 mediates the effects of LIV on wound healing, we used floxed Igf1 mice that allowed inducible knockdown of liver IGF1 following injection with AAV8-pTBG-Cre [25,[29][30][31]. We fed floxed Igf1 mice either ND or HFD for 4 months, the latter to induce a prediabetic state, then subjected each group to excisional wounding and either LIV or sham control treatment.…”