Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired. We can use the biologic basis of the fetal regenerative phenotype as a roadmap to recapitulate regenerative wound healing in adult skin. This would have significant impact for normal wound repair, as well as in impaired wound healing states, such as diabetes. Fetal wounds are characterized by an attenuated inflammatory response and a characteristic fibroblast-mediated ECM, that is composed of high molecular weight hyaluronan. The dermal fibroblast is a primary source of hyaluronan in fetal skin;conversely, in adult wounds, the fibroblast is the main mediator of scar formation. We hypothesize that there are cellular processes in fetal fibroblasts that regulate the regenerative phenotype, which are also present in fibroblasts resident in adult wounds but lack an appropriate stimulus. Our data suggests that interleukin-10 (IL-10) may be the initial stimulus that reactivates a regenerative phenotype in adult wounds. In addition to IL-10's accepted immuno-regulatory role, our preliminary data indicate a new mechanism for IL-10 in the fetal regenerative phenotype and that is regulation of the extracellular matrix, specifically hyaluronan synthesis. To elucidate the mechanisms by which IL-10 governs fetal regenerative healing and to determine whether activation of these same mechanisms in fibroblasts resident in adult wounds can recapitulate regenerative repair, we propose the following three aims:
Aim 1 : identify and characterize the effects of IL-10 on the fetal fibroblast formation of hyaluronan and elucidate a potential signaling pathway. After testing if this pathway that regulates the ECM is essential to the fetal wound healing phenotype, we can determine if IL-10 induction of hyaluronan synthesis can affect regenerative wound healing in adult wounds.
Aim 2 : use a series of novel transgenic mice to test if IL-10's effects are mediated via STAT3 dependent signaling in dermal fibroblasts and determine if the fibroblast is the key effector cell of IL-10's regenerative response.
Aim 3 : test if the IL-10 induced hyaluronan ECM is essential to enhancing cellular functions of the fibroblast and attenuating wound inflammation as part of the regenerative response. Lastly, using mouse models that are characterized by dysfunctional fibroblasts and altered wound inflammation, we will determine if IL-10 can correct these collective deficiencies and augment wound repair. For unknown reasons, the remarkable ability that we all possess to heal regeneratively in utero is lost in late gestation and instead defaults to a scarring phenotype. Completing our aims will yield fundamental insights and new knowledge into IL-10 biology and the recapitulation of fetal regenerative healing in adult wounds. This will offer significant possibilities to improve the care of patients who cope with the debilitating aspects of impaired wound healing quality and scar formation by the development of therapeutics that may have broad implications for regenerative tissue repair.

Public Health Relevance

The proposed research is relevant to the public health because the ability to regeneratively heal wounds with restored tissue integrity can potentially save some of the $25 billion spent annually on impaired wound healing. This proposal holds promise to advance our understanding of the cellular and molecular mechanisms of the fetal regenerative tissue repair and use it as roadmap to make progress toward the long-term goal of recapitulating regenerative wound healing in adult wounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Somers, Scott D
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Balaji, Swathi; Wang, Xinyi; King, Alice et al. (2017) Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling. FASEB J 31:868-881
Balaji, Swathi; Han, Nate; Moles, Chad et al. (2015) Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds. Surgery 158:846-56
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Balaji, Swathi; King, Alice; Marsh, Emily et al. (2015) The role of interleukin-10 and hyaluronan in murine fetal fibroblast function in vitro: implications for recapitulating fetal regenerative wound healing. PLoS One 10:e0124302