Wound repair and regeneration: mechanisms, signaling, and translation

Abstract

The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body's natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.

Fig. 1. Clinical features of most common wound-healing pathologies

The repair response can be disturbed by a multitude of local and systemic factors leading to diverse wound-healing pathologies. (A) Medial aspect of lower leg with venous leg ulcer (VLU). (B) Diabetic foot ulcer (DFU). (C) Lateral aspect of lower leg with an arterial ulcer. (D) Pressure sore. (E) Hypertrophic scar after thyroid surgery. (F) Keloid.

Fig. 2. Molecular and cellular mechanisms in normal skin repair

Illustrations show molecular and cellular mechanisms pivotal for progression of wound healing. Early stages of wound healing include hemostasis and activation of keratinocytes and inflammatory cells. The intermediate stage involves proliferation and migration of keratinocytes, proliferation of fibroblasts, matrix deposition, and angiogenesis. Late-stage healing involves remodeling of ECM, resulting in scar formation and restoration of barrier. This spatiotemporal process is tightly controlled by multiple cell types that secrete numerous growth factors, cytokines, and chemokines (listed below) to achieve closure and functional restoration of the barrier.

Fig. 3. Molecular pathology of chronic wounds

Illustrations show molecular and cellular mechanisms that are impaired in chronic wounds. (A) Chronic wounds show hyperproliferative and nonmigratory epidermis, unresolved inflammation, presence of infection, and biofilm formation. Although there is an increase in inflammatory cells (neutrophils and macrophages), not all are properly functioning. Uncontrolled proteases interfere with essential repair mechanisms. Some fibroblasts become senescent. In chronic wounds, there is a reduction of angiogenesis, stem cell recruitment and activation, and ECM remodeling compared with normal wound healing (Fig. 2). (B) Histologies representing characteristics of a diabetic foot (DFU), venous stasis (VLU), and pressure ulcers. Although different in etiology, these chronic wounds show common cellular features depicted in (A): H, hyperproliferative epidermis; F, fibrosis; I, increased cellular infiltrate (inflammation).

Fig. 4. Mechanisms and models of repair and regeneration are conserved

Activation of the immune response, angiogenesis, innervation, epithelialization, and scar formation are fundamental repair processes and are conserved between human (center, abdominal wound) and other multicellular organisms, which offer particular advantages for experimental investigation. Drosophila are highly genetically tractable and at embryonic stages are translucent, enabling live imaging of wound reepithelialization. This laser-wounded Drosophila embryo is expressing green fluorescent protein (GFP):actin (green) that reveals the cytoskeletal machineries of leading-edge epithelial cells in real time (arrows, actin cable; asterisks, filopodia). Zebrafish larvae are also translucent and have been used to investigate the dynamics of the wound inflammatory response in transgenic fish, such as this wounded fish expressing GFP: neutrophils (green) and red fluorescent protein (RFP):macrophages (red) to show how leukocytes are recruited to a wound (circled). The chick is a lesser used model, but has the advantage of easy accessibility during embryonic stages (in ovo, rather than in utero). A silver-stained section from a chick-limb wound reveals the cutaneous hyperinnervation (asterisks) triggered by wounding; the wound site is marked by carbon black particles (arrows). Rodents are the most frequently used models for wound healing studies despite having looser skin than humans. A hematoxylin and eosin (H&E)–stained section of a 3-day excisional wound on the dorsum of a mouse reveals the stage when a scab is still present (asterisks) and the inflammatory response apparent beneath the almost repaired epithelium (arrowheads) as it migrates at the interface between scab and granulation tissue.

Fig. 5. Human chronic wounds as a research resource

(A) Various types of biological materials can be collected from a chronic wound, including wound fluids, swabs, and tissue specimens. These fluids, cells, and tissues can support cellular and molecular analyses to better understand the chronic wound pathology and to identify biomarkers of wound healing and impairment. (B) Example analyses using tissue specimens. Genomic profiling and immunohistochemistry revealed distinct profiles of healing capacity. A biomarker of a healing phenotype, decreased nuclear β-catenin, has been identified in human wounds (178). Such methods can be used to identify margin of debridement (red line).