Yuval Rinkevich. Can skin wounds heal without leaving scars? That's the question being explored in a project entitled ScarLessWorld headed by Dr. His work will now be supported by a Consolidator grant from the European Research Council ERC providing around two million euros of research funding over the next five years.
Mechanisms underlying preferential ‘scarless’ wound healing in the oral mucosa
People have been fascinated by tissue and organ regeneration for thousands of years. He and his team have recently made a major contribution to this field. Rinkevich gives an example, "If the skin of a developing embryo gets injured, it simply regenerates. In later life stages, however, the wound scars. The proportion of regenerative cells decreases as development progresses, whilst the number of scar-forming cells increases. When the researchers transplanted fibroblasts from mouse embryos into wounds in adult animals, scarring was significantly reduced.
Building on these results, Yuval Rinkevich knows what he wants to achieve next, "We want to use new experimental approaches to understand how this scarless wound healing works and, in the long-term, to reproduce it clinically. Patients with visible scars, particularly on the face, suffer from social stigma and psychological trauma Brown et al.
However, most commercial wound healing products fail to initiate skin regeneration. In the s, experiments in fetal lambs demonstrated the ability to heal skin without scarring in early gestation Burrington, In each instance, cutaneous wounds made prior to the transition to the adult skin scarring phenotype resulted in complete organ regeneration, including the development of dermal appendages Walmsley et al.
In a subsequent series of reciprocal translocation experiments, tissue transplanted between postnatal and fetal animals implicated a cell intrinsic mechanism to the scarless wound healing phenomenon Longaker et al. For patients, scarless skin wound healing would allow complete functional recovery from burns, surgical incisions, and major tissue loss from trauma or other causes.
In the pediatric population, this would mean contractures limiting normal growth and development could be avoided. As such, research into the mechanism behind fetal scarless wound healing has expanded significantly. Below, we discuss the known mechanisms of adult fibrosis and fetal scarless wound healing. Through our discussion, we hope to elucidate promising clinical targets and critically evaluate therapies currently in practice. To understand skin wound healing, a basic understanding of skin anatomy and embryology is necessary.
The skin, or integumentary system, is a complex organ that provides a moisture and microbial barrier to the outside world. It is divided into several basic layers that can then be subdivided further by cellular differentiation and cell types. The most superficial layer of the skin is the epidermis. The epidermis is formed from a thin layer of embryonic ectoderm. After neuralization occurs in the fetus, the single cell layer of simple ectoderm expands to become a simple squamous epithelium known as the periderm.
The outermost layer stratum corneum sheds and sloughs off in adults.
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In the fetus, the development of the stratum corneum leads to the eventual shedding of the periderm. The epidermis contains a deep layer of cells, known as basal cells, that serve as a stem cell reservoir for the development and differentiation of keratinocytes. Keratinocytes get their name from keratin, the characteristic protein of the epidermis. Keratinocytes begin their lifecycle at the basement membrane and gradually migrate up through the epidermis to the surface of the skin; where they expel their nuclei and flatten to form a stratified squamous epithelium.
Below the epidermis lies the dermis, a thick layer rich in extracellular matrix ECM proteins. The dermis houses the base of epidermal appendages, such as hair follicles, sweat glands, and also houses dermal fibroblasts. Fibroblasts deposit both normal and scar ECM proteins, which give the skin its tensile strength. Additionally, nerves and muscles are found in the dermis. The dorsal, ventral, and cranial dermis have different embryonic origins, though all mesodermal.
The ventral dermis is derived from the somatic layer of lateral plate mesoderm while the cranial dermis is derived from the neural crest. In the dorsal dermis, cells are derived from the dermamyotome subdivision of somites. During fetal development, the dermis develops upward projections toward the epidermis known as dermal papillae, while the epidermis develops downward projections into the dermis, known as epidermal ridges rete ridges. From the epidermal ridges, several specialized epidermal structures develop, including hair, sebaceous glands, accrine sweat glands, apocrine sweat glands, mammary glands, teeth, and nails.
Sebaceous glands secrete sebum, an oily substance that lubricates the skin and hair. Accrine sweat glands are widely distributed and function to secrete thermoregulatory sweat, while apocrine sweat glands secrete odorous substances and are located mostly in the axilla and pubic regions in humans. Hair is formed by an epidermal ridge that is indented at the bottom by a dermal papilla. Overlying the dermal papilla is the germinal matrix, a proliferating ectoderm that forms the base of the hair bulb. The germinal matrix undergoes a specialized keratinization process which leads to the development of a hair shaft that protrudes through the inner and outer epidermal root sheath.
Hair color is produced by melanocytes secreting melanin at the base of the hair bulb. Progenitor cells for the hair follicle are located within the hair follicle bulge region. These cells differentiate and migrate from the bulge downward into the follicle to participate in hair follicle growth phases. Sebaceous glands in most parts of the body are associated with and bud off of the hair follicle shaft as a diverticula.
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The gland then expands into the dermis where it branches to form secretory acini or alveoli. In sebaceous glands, the proliferating stem cell population resides in the basal layer. The basal layer stem cells then divide and differentiate to supply the gland with a constant source of new mature secretory epithelial cells.
Below the dermis is the hypodermis. The hypodermis is a layer of subcutaneous fat containing the skin's perforating blood vessels and adipose tissue. Blood vessels in the skin arise from deeper muscle tissue and then penetrate the dermis and epidermis. In the dermis and epidermis, blood vessels give off fine capillary tributaries to supply skin cells with necessary oxygen and nutrients. Melanin also serves as a natural sunscreen. Our understanding of the formation of scar tissue is inseparably linked to the process of normal wound healing.
In clinical and experimental practice, specific elements of the wound healing process are usually targeted to reduce scar formation. However, it is likely that every event in the wound healing cascade contributes in some way to the eventual formation of scar tissue. Human skin wound healing is often described in three overlapping stages: inflammation, proliferation, and remodeling Gurtner et al. The inflammatory phase involves the influx of a diverse array of cells, including neutrophils, macrophages, and lymphocytes, that cleanse the wound space of bacteria, debris, and dead cells Gurtner et al.
These cells also release a mixture of cytokines that regulate the behavior of other cells and allow the wound healing process to continue Box 1. Not mentioned in the introduction of adult skin healing is the importance of macrophages in wound healing. Eliminating inflammatory cells has minimal effect on wound healing, except in the case of macrophages. Macrophages are thought to have a regulatory role in the process of wound healing.
Macrophages appear to be responsible for recruiting inflammatory cells into the wound, for initiating dermal proliferation, and for determining collagen subtype deposition. The inflammatory phase is followed by the proliferative phase, during which fibroblasts create and organize collagen and other ECM molecules to form new tissue. In adult wounds, new collagen is laid down in parallel tightly spaced bundles. Another characteristic of human scar tissue is that the dermal appendages in normal skin, including hair follicles and sweat glands, do not regenerate and are not present Gurtner et al.
The absence of these appendages may have implications for the regeneration of tissue during healing, since stem cells residing within these structures contribute to skin regeneration under homeostatic and injured conditions Plikus et al. The final remodeling phase of wound healing takes place over months to years and involves the gradual structural evolution of the scar tissue.
Additionally, scars contract to reduce their overall size. Lastly, the tensile strength of scarred skin increases as remodelling occurs, but never reaches the full strength of uninjured skin Levenson et al. Surgical incisions in a mammalian fetus heal rapidly without scar formation Burrington, and are nearly indistinguishable from uninjured tissue Beanes et al. In , the same observation was reported in human fetuses Rowlatt, The most significant advances were made in the late s through a series of experiments delineating the differences between adult and fetal wound healing in lambs Longaker et al.
However later experiments showed that these factors are not sufficient, and that scarless healing is intrinsic to fetal tissue Longaker et al.
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Current efforts in the field of scarless healing are aimed at identifying factors intrinsic to fetal tissue that allow for scarless healing. Inherently, fetal wound healing is difficult to study because the fetus develops in the protective and closed environment of the uterus. Healing fetal wounds contain far fewer inflammatory cells compared with adult wounds Longaker et al. The absence of these cells likely results in a very different microenvironment with respect to cytokine and growth factor expression, and this may influence fibroblasts to lay down ECM molecules in a regenerative rather than scarring pattern.
Hyaluronic acid is present in greater concentrations in fetal wounds Longaker et al. These molecules likely interact with cells involved in healing and may encourage a regenerative phenotype. There is also a higher level of matrix metalloproteinase activity in fetal wounds, which may allow for early remodeling of skin wounds and scar collagen Dang et al.
Fibroblasts deposit ECM molecules, whose configuration is an important element of regenerated versus scarred tissue. Therefore, it is possible that changes in fibroblasts populations or fibroblast phenotype in the wound play a role in the loss of scarless healing.
Additionally, fetal fibroblasts are capable of proliferating while simultaneously depositing collagen, whereas adult fibroblasts undergo proliferation in the wound and then later deposit collagen Larson et al. Rinkevich et al. Of note, En1 is only expressed early in development, and allows only for lineage tracing these cells. Further studies will determine the extent to which these transcriptional differences contribute to regenerative versus scarring healing Box 2. CD26 is a major identifying cell surface marker in the scar fibroblasts derived from En1 embryonic skin cells.
When CD26 is targeted with a specific inhibitor, diprotin A, wounds will heal with significantly diminished scar collagen production. CD26 may also identify human scar fibroblasts and could be used as a therapeutic target. In adult mammals, the oral mucosa represents a model of regenerative healing, where injury results in minimal to no scar formation. The attenuated inflammatory microenvironment of the oral mucosa may partially explain the reduction in scar formation. But also, ECM composition prior to wounding may be a major contributor to scarless healing.
Conversely, the presence of elastin is more pronounced in the skin than the oral mucosa. Though WNT activates three separate and independent signaling cascades, canonical WNT signaling has been the major focus of wound healing research and scarless fetal healing. This class of secreted glycoproteins, of which humans have 19 individual subtypes, acts on cells locally to regulate proliferation and differentiation Leavitt et al. TCF then activates transcription of several growth factors involved in embryonic development, organogenesis, and tissue repair and regeneration Houschyar et al.
In adult dermal tissue, many WNT proteins WNT 1, 3, 4, 5, and 10 —both canonical and otherwise—are activated during normal wound healing, similar to cell proliferation signals for dermal fibroblasts and keratinocytes Whyte et al. WNT responsive cells in dermal tissue include hair follicle bulge cells, basal interfollicular epidermal cells, and dermal fibroblasts. Coming from these studies, recombinant WNT proteins have emerged as a potential therapeutic Whyte et al.
The transforming growth factor beta TGFB superfamily receives attention for its ability as a ubiquitous growth factor in mammalian wound healing. These proteins, while having striking structural homology, are thought to exhibit different and potentially competing actions in the wound environment.
In vivo , the TGFB subtypes have specific temporal and spatial distributions—potentially indicating their individual roles in wound healing and regenerative repair. Also, an important part of TGFB function is that it can bind to and be stored on the ECM, where until cleaved by serum proteases, it remains quiescent and as an indolent reservoir for augmenting wound healing when provoked by injury Lichtman et al.
TGFB1 also plays an important role in the early phases of adult wound healing after being released from activated platelets. TGFB3, however, may play a role in fetal scarless wound healing Lichtman et al. In the adult wound environment, TGFB3 appears in the early and later phases of wound healing where it aids in macrophage recruitment, ECM deposition, and may reduce cell proliferation. However, recent studies highlight the importance of each of the TGFB subtypes in adult and fetal wound healing.
While proportions of TGFB subtypes do differ in fetal and adult wounds, attempting to alter these ratios does not significantly impact adult wound healing. Yet, adult wounds treated with TGFB1 inhibitors tend to heal with an improved appearance and smaller resultant scars, while those treated with recombinant TGFB3 reveal the same outcome Shah et al. Attempts at enhancing expression or delivery of TGFB proteins are unsuccessful to date.
Between and , Avotermin received press as a recombinant TGFB3 for improved scar formation in acute wounds and scar revisions So et al. Unfortunately, this product failed phase III clinical trials and has subsequently been abandoned. Ultimately, study of the TGFB pathway is necessary for achieving a complete understanding of the wound healing mechanism. Another important group of growth factors in wound healing are the fibroblast growth factors FGFs. FGFs target fibroblasts and several other cell types involved in wound healing to induce proliferation, differentiation, and cell migration.
In the fetus, FGFs are highly involved in organogenesis and cell differentiation. Locally in the adult, FGFs influence wound healing by creating feedback loops to initiate fibroblast growth and differentiation. As a result of these findings, current experimental treatments with FGF9 focus on male patterned baldness Fan et al. However, FGF9 may also be an important new target for wound healing since it is the only small molecule capable of regenerating skin appendages.
The subunits of HIF1 bind together to acquire transcriptional properties, allowing it to regulate the transcriptional activity of hundreds of genes that promote cell survival in hypoxic conditions. A master regulator of oxygen homeostasis, HIF1 acts predominantly under hypoxic conditions, such as in the wound bed with its disrupted vascular supply.
In normal tissue oxygen conditions, HIF1A is rapidly and continuously degraded following translation Tamama et al. Tissue hypoxia, however, induces a sustained increase in the expression of HIF1A. Pathologic scars, including keloid and hypertrophic scars, are the result of an excessive fibrotic response that surpasses the rate of remodeling Craig, Consistent elevation of HIF1A protein levels resulting from increased transcription and translation, followed by stabilization of the HIF1A subunit, is observed in keloid and scleroderma tissues compared with normal skin Distler et al.
Translation of targeted HIF1A inhibition for scarless wound healing necessitates that future studies evaluate therapeutically useful HIF1A inhibitors and exclude cytotoxic compounds. Vascular endothelial growth factor VEGF is a key factor in angiogenesis, another important component of wound healing. It is a homodimeric glycoprotein that regulates the permeability of blood vessels. Several recent studies suggest a link between the surplus capillary growth seen in healing wounds and scar formation. More recent studies suggest an association of robust capillary growth with the development of keloids Mogili et al.
Moreover, a recent comparison of capillary content in human normotrophic and hypertrophic scars demonstrated that hypertrophic scar formation is associated with higher levels of angiogenesis van der Veer et al. It is the first angiogenesis inhibitor approved by the U. Food and Drug Administration for the prevention of tumor growth and it is widely used in the management of diabetic retinopathy. Although bevacizumab reduces scar formation, it does have adverse effects including headache, high blood pressure, increased risk of bleeding, and intestinal perforation. Unfortunately, the effects of TNFA modulation on human wound healing are less studied.
Several of the wounds demonstrated healing during the study period, and the degree of healing correlated with a reduction of TNF staining seen on immunohistochemical examination of wound biopsies. Interleukins are cytokines that regulate the function of immune cells. As such, they are ideal targets to mediate inflammation and ultimately wound healing.
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As such, pharmacologic antagonism of the IL1 receptor IL1R could prove beneficial in the development of scarless wound healing products. Several studies demonstrate that fetal skin expresses increased IL10 relative to adult skin Gordon et al. In clinical trials, IL10 has been shown to reduce scar formation in murine Gordon et al. Though the ideal timing and dosing of IL10 administration has not yet been determined in humans, studies suggest that scar appearance is optimized with low concentrations of IL10 administered multiple times over the course of scar maturation, likely influencing scar remodeling over time Kieran et al.
Additional studies could further legitimatize IL10 as a wound healing therapy. Molecular inhibition of LO during wound healing reportedly results in diminished tensile strength in addition to collagen content. However, further studies are necessary to evaluate the efficacy of these compounds, as they have yet to be tested using appropriate in vivo models of excisional wound healing or hypertrophic scar formation.