Interleukin‐10–mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolismviafibroblast‐specific STAT3 signaling

Abstract

The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)–dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox–mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3-knockdown postnatal mice—plus syngeneic fibroblast cell-transplant models—we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10–induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.—Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10–mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.

IL-10 Promotes Endothelial Progenitor Cell Driven Wound Neovascularization and Enhances Healing via STAT3

“…To further determine whether these effects of IL-10 were mediated via conserved STAT3 signaling, we used a tamoxifen (4-OHT)-inducible cre driven skin-specific STAT3 knockout murine model. We generate the STAT3 Δ/Δ transgenic mice as described previously 54 . Topical application of 4-OHT in vegetable oil as a vehicle down regulated STAT3 levels in the skin of these mice, compared to topical application of vegetable oil vehicle alone, which served as vehicle control for all experimental purposes (Figure S1).…”

“…Taken together, these data support our prediction that IL-10 overexpression improves initial wound closure and granulation tissue deposition by mechanisms that are STAT3 dependent, ultimately leading to superior remodeling and regeneration phenotype that we have recently reported. 54…”

“…We and others have shown that IL-10 overexpression regulates inflammatory responses to promote a regenerative wound healing phenotype in murine cutaneous wounds in a dose-dependent manner. 51–53 Furthermore, we have recently reported a novel role for IL-10 in inducing a fibroblast- mediated formation of an extracellular wound matrix rich in hyaluronan 54 , which proved to be essential for IL-10’s regenerative wound healing capability. Several other studies have also shown that IL-10 regulates the synthesis and degradation of various extracellular matrix molecules in different fibroblastic cell types, which upholds the notion of potential IL-10 anti-fibrotic mechanisms in the skin 67–69 .…”

“…50 Although these collective findings support the role of IL-10 in EPC-mediated neovascularization, the mechanisms that determine such a function in cutaneous wounds remain to be elucidated. We and others have shown that, in non-diabetic wound healing, IL-10 overexpression in postnatal cutaneous dermal wounds induces regenerative (scarless) tissue repair via inflammatory regulation 51–53 and the fibroblast-mediated formation of a extracellular wound matrix rich in hyaluronan 54 through a STAT3- dependent signaling pathway. 55,56 .…”

Current concepts on how to optimise Skin Needling 2020: A personal experience: Part 2

“…Research shows that natural hyaluronic acid does promote better scar formation 24,25 and has been implicated in assisting scarless healing. 26 I researched the value of hyaluronic acid immediately after needling starting 2007 and while I could not distinguish any special advantages in long-term results, the patients were much more comfortable in the immediate postneedling phase. In a half-face pilot study in 2008 only one side of the face was treated with hyaluronic acid as a simple application.…”