Developmental Models for Wound Healing

Abstract

The bodies of animals and humans frequently sustain damage as a result of injury or disease, and the ability to repair this damage is essential for life. Tissue repair, or wound healing, is a complex process which is difficult to study experimentally and is, therefore, not fully understood. Over recent years, various studies have identified striking similarities between tissue repair and the process of morphogenesis in which tissues are originally formed during embryonic development. This has raised the possibility of using developmental processes as model systems to help in better understanding of tissue repair. This article describes how comparative studies of embryonic morphogenesis and tissue repair have improved understanding of the mechanisms of repair. The article further discusses the key processes and regulatory mechanisms that are shared between development and repair, including important recent developments in the field.

Key Concepts:

  • The behaviour of cells during the repair of damaged tissues often parallels that observed when tissues are initially formed during embryogenesis.

  • Developmental processes such as Drosophila dorsal closure and mouse eyelid closure can be used as models to help in understanding of wound healing.

  • Common cytoskeletal and signalling machineries regulate cell behaviour during the reepithelialisation episode of wound healing and also during developmental epithelial closure events.

  • Key regulators of epithelial closure include the Rho GTPases, the JNK cascade and the planar cell polarity pathway.

  • Coordinated collective migration of many cells is necessary for both wound healing and developmental epithelial remodelling.

  • Mechanical signalling seems to be important for tissue remodelling, but its molecular mechanisms still largely remain elusive.

  • Inflammatory cells play instructive roles during tissue remodelling.

  • Novel techniques such as advanced bioimaging and mathematical modelling will help to uncover the general mechanisms underpinning wound healing and developmental tissue remodelling.

Keywords: wound healing; similarities between tissue formation and repair; dorsal closure; eyelid closure; neural tube closure; Rho GTPases; JNK; planar cell polarity (PCP) pathway; collective cell migration; biomechanics of epithelial closure

Figure 1.

Wound healing. (a) Adult mouse skin 3 days postwounding, stained with haematoxylin and eosin. Gr, granulation tissue; ET, epithelial tongue, the cohort of epidermal cells moving underneath the scab to cover the defect. Image courtesy of Nichola Cooper and Matthew Hardman. © Nichola Cooper and Matthew Hardman. (b) Time‐lapse images of ‘purse‐string’ wound healing of the Drosophila embryonic epidermis. F‐actin is visualised. A contractile actomyosin cable formed at the leading edge constricts to pull the wound closed. Scale bars=5 mm (a); 10 µm (b).

Figure 2.

Developmental epithelial closures that are recapitulated by wound healing. (a) Drosophila dorsal closure. F‐actin is visualised in green in the lower panels. The edges of lateral epidermis are brought together to replace the amnioserosa. Contraction of an actomyosin cable at the epidermal leading edge contributes to closure of the gap, whereas filopodia assist adhesion of the epithelial edges at the end of closure. (b) Mouse eyelid closure. Primitive eyelids migrate over the cornea to cover the embryonic eye. (c) Genetic disruption of eyelid closure. Wild‐type mice are born with their eyes closed due to the process of eyelid closure (control). However, ROCK‐I knockout mice fail in eyelid closure and are consequently born with the ‘eyelids‐open‐at‐birth’ phenotype (ROCK KO).

Images in (b) and (c) were modified from Shimizu et al.2005 with permission from Rockefeller University Press. © 2005 Rockefeller University Press.
Figure 3.

The JNK pathway. A diagram illustrating the conserved JNK signalling cascades of mammals and Drosophila. Homologous proteins are depicted in the same colour and shape. JNKs are phosphorylated and activated by upstream JNK kinase (JNKK) and JNK kinase kinase (JNKKK). Then activated JNK phosphorylates many different substrates including c‐Jun, which binds to c‐Fos and constitutes the AP‐1 transcription factor. Both mammalian and DrosophilaJNK cascades play pivotal roles in multiple epithelial closure events, including wound healing, eyelid closure, neural tube closure and dorsal closure. Abbreviations: Slpr, Slipper; Hep, Hemipterous; Bsk, Basket; Kay, Kayak (Drosophila Fos). For details, see the main text and Xia and Karin .

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Further Reading

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How to Cite close
Matsubayashi, Yutaka, and Millard, Tom H(Sep 2013) Developmental Models for Wound Healing. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021306]