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Scarless wound healing: finding the right cells and signals

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Abstract

From the moment we are born, every injury to the skin has the potential to form a scar, many of which can impair form and/or function. As such, scar management constitutes a billion-dollar industry. However, effectively promoting scarless wound healing remains an elusive goal. The complex interactions of wound healing contribute to our inability to recapitulate scarless wound repair as it occurs in nature, such as in fetal skin and the oral mucosa. However, many new advances have occurred in recent years, some of which have translated scientific findings from bench to bedside. In vivo lineage tracing has helped establish a variety of novel cellular culprits that may act as key drivers of the fibrotic response. These newly characterized cell populations present further targets for therapeutic intervention, some of which have previously demonstrated promising results in animal models. Here, we discuss several recent studies that identify exciting approaches for diminishing scar formation. Particular attention will also be paid to the canonical Wnt/β-catenin signaling pathway, which plays an important role in both embryogenesis and tissue repair. New insights into the differential effects of Wnt signaling on heterogeneous fibroblast and keratinocyte populations within the skin further demonstrate methods by which wound healing can be re-directed to a more fetal scarless phenotype.

Recent approaches to reducing scar formation. Representation showing novel scientific approaches for decreasing scar formation, including the targeting of pro-fibrotic cell populations based on surface molecule expression (e.g. DPP4+ fibroblasts, ADAM12+ pericytes). Modulation of cellular mechanotransduction pathways are another means to reduce scar formation, both at the molecular level or, macroscopically with dressings designed to offload tension, at cutaneous wound sites (ADAM12 a disintegrin and metalloprotease 12, DPP4 dipeptidyl peptidase-4, FAK focal adhesion kinase)

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Authors and Affiliations

  1. Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA 94305-5461, USA

    Tripp Leavitt, Michael S. Hu, Clement D. Marshall, Leandra A. Barnes, H. Peter Lorenz & Michael T. Longaker

  2. Boston University School of Medicine, Boston, MA, USA

    Tripp Leavitt

  3. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Michael S. Hu & Michael T. Longaker

  4. Department of Surgery, John A. Burns School of Medicine, University of Hawai’i, Honolulu, HI, USA

    Michael S. Hu

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  1. Tripp Leavitt
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  2. Michael S. Hu
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Correspondence to Michael T. Longaker.

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This work was supported in part by the California Institute for Regenerative Medicine (CIRM) Clinical Fellow training grant TG2-01159 (to M.S.H.), the Stanford University School of Medicine Transplant and Tissue Engineering Fellowship Award (to M.S.H.), the American Society of Maxillofacial Surgeons (ASMS)/Maxillofacial Surgeons Foundation (MSF) Research Grant Award (to M.S.H., H.P.L., and M.T.L.), the American College of Surgeons Resident Research Scholarship (to C.D.M.), the Howard Hughes Medical Institute (to L.A.B.), NIH grant R01 GM087609 (to H.P.L.), a gift from Ingrid Lai and Bill Shu in honor of Anthony Shu (to H.P.L.), the Hagey Laboratory for Pediatric Regenerative Medicine and The Oak Foundation (to H.P.L. and M.T.L.), NIH grant U01 HL099776 (to M.T.L.), and the Gunn/Olivier fund (to M.T.L.).

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Leavitt, T., Hu, M.S., Marshall, C.D. et al. Scarless wound healing: finding the right cells and signals. Cell Tissue Res 365, 483–493 (2016). https://doi.org/10.1007/s00441-016-2424-8

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