Clinical Features and Mechanisms of Differential Wound Healing and Scarring Across Anatomical Sites

<b>Significance:</b> Fibrosis is associated with high rates of morbidity and mortality and poses a heavy burden on the health care system. Different regions of the body heal at different rates with varying degrees of fibrosis, with regions such as the extremities and trunk being more prone to scarring than the face and mucosa. Therapies that leverage the unique mechanisms underlying these anatomical differences in wound healing may be effective in mitigating fibrosis and scarring. <b>Recent Advances:</b> Recent studies in mice have revealed fibroblast-intrinsic signaling pathways that contribute to scar formation in different areas of the body, such as engrailed-1-positive fibroblasts and paired-related homeobox-1-positive fibroblasts in dorsal, ventral, and dermal scars, respectively. Novel approaches that target specific molecular pathways within fibroblasts may pave the way for effective therapies in replicating features of scar-resistant skin and facilitating wound healing. <b>Critical Issues:</b> Clinical practice and animal studies have shown some body regions to be more susceptible to fibrosis than others. However, our understanding on cellular and molecular mechanisms that contribute to this phenomenon remains limited. <b>Future Directions:</b> Advances in antiscarring therapy will benefit from harnessing several aspects of wound healing in regions less prone to fibrosis, including reducing mechanical tension, controlling angiogenic response, and modulating fibroblast subtypes. [Figure: see text] [Figure: see text].