Elastin signaling in wound repair

Skin is an important organ to the human body as it functions as an interface between the body and environment. Cutaneous injury elicits a complex wound healing process, which is an orchestration of cells, matrix components, and signaling factors that re‐establishes the barrier function of skin. In adults, an unavoidable consequence of wound healing is scar formation. However, in early fetal development, wound healing is scarless. This phenomenon is characterized by an attenuated inflammatory response, differential expression of signaling factors, and regeneration of normal skin architecture. Elastin endows a range of mechanical and cell interactive properties to skin. In adult wound healing, elastin is severely lacking and only a disorganized elastic fiber network is present after scar formation. The inherent properties of elastin make it a desirable inclusion to adult wound healing. Elastin imparts recoil and resistance and induces a range of cell activities, including cell migration and proliferation, matrix synthesis, and protease production. The effects of elastin align with the hallmarks of fetal scarless wound healing. Elastin synthesis is substantial in late stage in utero and drops to a trickle in adults. The physical and cell signaling advantages of elastin in a wound healing context creates a parallel with the innate features of fetal skin that can allow for scarless healing. Birth Defects Research (Part C) 96:248–257, 2012. © 2012 Wiley Periodicals, Inc.     

Matrix metalloproteinases and epidermal wound repair

Epidermal wound healing is a complex and highly coordinated process where several different cell types and molecules, such as growth factors and extracellular matrix (ECM) components, play an important role. Among the many proteins that are essential for the restoration of tissue integrity is the metalloproteinase (MMP) family. MMPs can act on ECM and non-ECM components affecting degradation and modulation of the ECM, growth-factor activation and cell–cell and cell–matrix signalling. MMPs are secreted by different cell types such as keratinocytes, fibroblasts and inflammatory cells at different stages and locations during wound healing, thereby regulating this process in a very coordinated and controlled way. In this article, we review the role of MMPs and their inhibitors (TIMPs), as well as the disintegrin and metalloproteinase with the thrombospondin motifs (ADAMs) family, in epithelial wound repair.     

Matrix remodeling by MMPs during wound repair

Repair following injury involves a range of processes – such as re-epithelialization, scar formation, angiogenesis, inflammation, and more – that function, often together, to restore tissue architecture. MMPs carry out diverse roles in all of these activities. In this article, we discuss how specific MMPs act on ECM during two critical repair processes: re-epithelialization and resolution of scar tissue. For wound closure, we discuss how two MMPs – MMP1 in human epidermis and MMP7 in mucosal epithelia – facilitate re-epithelialization by cleaving different ECM or ECM-associated proteins to affect similar integrin:matrix adhesion. In scars and fibrotic tissues, we discuss that a variety of MMPs carry out a diverse range of activities that can either promote or limit ECM deposition. However, few of these MMP-driven activities have been demonstrated to be due a direct action on ECM.     

Neutrophil signaling during myocardial infarction wound repair

Neutrophils are key effector cells of the innate immune system, serving as a first line of defense in the response to injury and playing essential roles in the wound healing process. Following myocardial infarction (MI), neutrophils infiltrate into the infarct region to propagate inflammation and begin the initial phase of cardiac wound repair. Pro-inflammatory neutrophils release proteases to degrade extracellular matrix (ECM), a necessary step for the removal of necrotic myocytes as a prelude for scar formation. Neutrophils transition their phenotype over time to regulate MI inflammation resolution and stabilize scar formation. Neutrophils contribute to the evolution from inflammation to resolution and scar formation by serving anti-inflammatory and repair functions. As anti-inflammatory cells, neutrophils contribute ECM proteins during scar formation, in particular fibronectin, galectin-3, and vimentin. The diverse and polarizing functions that contribute to MI wound repair make this innate immune cell a viable target to improve MI outcomes. Thus, understanding the signaling involved in neutrophil physiology in the context of MI may help to identify novel therapeutic targets.     

Pathological axes of wound repair: Gastrulation revisited

Post-traumatic inflammation is formed by molecular and cellular complex mechanisms whose final goal seems to be injured tissue regeneration. In the skin -an exterior organ of the body- mechanical or thermal injury induces the expression of different inflammatory phenotypes that resemble similar phenotypes expressed during embryo development. Particularly, molecular and cellular mechanisms involved in gastrulation return. This is a developmental phase that delineates the three embryonic germ layers: ectoderm, endoderm and mesoderm. Consequently, in the post-natal wounded skin, primitive functions related with the embryonic mesoderm, i.e. amniotic and yolk sac-derived, are expressed. Neurogenesis and hematogenesis stand out among the primitive function mechanisms involved. Interestingly, in these phases of the inflammatory response, whose molecular and cellular mechanisms are considered as traces of the early phases of the embryonic development, the mast cell, a cell that is supposedly inflammatory, plays a key role. The correlation that can be established between the embryonic and the inflammatory events suggests that the results obtained from the research regarding both great fields of knowledge must be interchangeable to obtain the maximum advantage.     

A role for endogenous glucocorticoids in wound repair

Exogenous glucocorticoids are known to inhibit wound repair, but the roles and mechanisms of action of endogenous glucocorticoids during the healing process are as yet unknown. Therefore, we wounded mice expressing a DNA-binding-defective mutant version of the glucocorticoid receptor (GR^dim mice) and also analysed fibroblasts from these animals in vitro. We found a remarkably enlarged granulation tissue with a high fibroblast density in GR^dim mice. This difference is likely to result from an increased migratory and proliferative capacity of GR^dim fibroblasts and from elevated expression levels of soluble factors involved in granulation tissue formation in wounds of GR^dim mice. In spite of the larger granulation tissue seen in early wounds, late wounds appeared normal, most likely due to an enhanced ability of GR^dim fibroblasts to contract collagen. These results demonstrate an as yet unidentified role of endogenous glucocorticoids in the regulation of wound repair.     

EGF and TGF-alpha in wound healing and repair

Wound healing is a localized process which involves inflammation, wound cell migration and mitosis, neovascularization, and regeneration of the extracellular matrix. Recent data suggest the actions of wound cells may be regulated by local production of peptide growth factors which influence wound cells through autocrine and paracrine mechanisms. Two peptide growth factors which may play important roles in normal wound healing in tissues such as skin, cornea, and gastrointestinal tract are the structurally related peptides epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). EGF/TGF-alpha receptors are expressed by many types of cells including skin keratinocytes, fibroblasts, vascular endothelial cells, and epithelial cells of the GI tract. In addition, EGF or TGF-alpha are synthesized by several cells involved in wound healing including platelets, keratinocytes, and activated macrophages. Healing of a variety of wounds in animals and patients was enhanced by treatment with EGF or TGF-alpha. Epidermal regeneration of partial thickness burns on pigs or dermatome wounds on patients was accelerated with topical application of EGF or TGF-alpha, and EGF treatment accelerated healing of gastroduodenal ulcers. EGF also increased tensile strength of skin incisions in rats and corneal incisions in rabbits, cats, and primates. Additional research is needed to better define the roles of EGF, TGF-alpha and their receptor in normal wound healing, to determine if alterations have occurred in the EGF/TGF-alpha system in chronic wounds, and optimize vehicles for effective delivery of peptide growth factors to wounds.     

脐血干细胞与创面修复

脐血干细胞是一类具有多向分化潜能的原始祖细胞,具备自我更新和增殖的能力,在特定条件诱导下可以分化为不同细胞,逐渐作为临床组织工程的来源细胞。近年来随着对脐血干细胞的不断研究,发现其在创面修复中具有明显的优势,成为创面临床治疗的一条新途径。本文从脐血干细胞的生物学特性、采集与冻存、体外扩增等方面对创面修复的研究进行综述。     

Scarless skin wound repair in the fetus.

The ability of a fetus to heal without scar formation depends on its gestational age at the time of injury and the size of the wound defect. In general, linear incisions heal without scar until late in gestation whereas excisional wounds heal with scar at an earlier gestational age. The profiles of fetal proteoglycans, collagens, and growth factors are different from those in adult wounds. The less-differentiated state of fetal skin is probably an important characteristic responsible for scarless repair. There is minimal inflammation in fetal wounds. Fetal wounds are characterized by high levels of hyaluronic acid and its stimulator(s) with more rapid, highly organized collagen deposition. The roles of peptide growth factors such as transforming growth factor-beta and basic fibroblast growth factor are less prominent in fetal than in adult wound healing. Platelet-derived growth factor has been detected in scarless fetal skin wounds, but its role is unknown. An understanding of scarless tissue repair has possible clinical application in the modulation of adult fibrotic diseases and abnormal scar-forming conditions.     

脐血干细胞与创面修复

脐血干细胞是一类具有多向分化潜能的原始祖细胞,具备自我更新和增殖的能力,在特定条件诱导下可以分化为不同细胞,逐渐作为临床组织工程的来源细胞。近年来随着对脐血干细胞的不断研究,发现其在创面修复中具有明显的优势,成为创面临床治疗的一条新途径。本文从脐血干细胞的生物学特性、采集与冻存、体外扩增等方面对创面修复的研究进行综述。     

Bombesin: a possible role in wound repair

During tissue regeneration and wound healing of the skin, migration, proliferation and differentiation of keratinocytes are important processes. Here we assessed the effect of a neuropeptide, bombesin, on keratinocytes during regeneration from scratch wounding. Bombesin purified from amphibian skin, is homologous of mammalian gastrin-releasing peptide and is active in mammals. Its pharmacological effects mediate various physiological activities: hypertensive action, stimulating action on gastric secretion, hyperglycemic effect or increased insulin secretion. In vitro it shows a hyperproliferative effect on different experimental models and is involved in skin repair. The aim of this study was to elucidate the effect of Bombesin in an in vitro experimental model on a mechanically injured human keratinocyte monolayer. We evaluated different mediators involved in wound repair such as IL-8, TGFbeta, IL-1, COX-2, VEGF and Toll-like receptors 2 and 4 (TLR2 and TLR4). We also studied the effects of bombesin on cell proliferation and motility and its direct effect on wound repair by observing the wound closure after mechanical injury. The involvement of the bombesin receptors neuromedin receptor (NMBR) and gastrin-releasing peptide receptor (GRP-R) was also evaluated. Our data suggest that bombesin may have an important role in skin repair by regulating the expression of healing markers. It enhanced the expression of IL-8, TGFbeta, COX-2 and VEGF. It also enhanced the expression of TLR2, while TLR4 was not expressed. Bombesin also increased cell growth and migration. In addition, we showed that NMBR was more involved in our experimental model compared to GRP-R.     

Epithelial stem cells and implications for wound repair

Activation of epithelial stem cells and efficient recruitment of their proliferating progeny plays a critical role in cutaneous wound healing. The reepithelialized wound epidermis has a mosaic composition consisting of progeny that can be traced back both to epidermal and several types of hair follicle stem cells. The contribution of hair follicle stem cells to wound epidermis is particularly intriguing as it involves lineage identity change from follicular to epidermal. Studies from our laboratory show that hair follicle-fated bulge stem cells commit only transient amplifying epidermal progeny that participate in the initial wound re-epithelialization, but eventually are outcompeted by other epidermal clones and largely disappear after a few months. Conversely, recently described stem cell populations residing in the isthmus portion of hair follicle contribute long-lasting progeny toward wound epidermis and, arguably, give rise to new interfollicular epidermal stem cells. The role of epithelial stem cells during wound healing is not limited to regenerating stratified epidermis. By studying regenerative response in large cutaneous wounds, our laboratory uncovered that epithelial cells in the center of the wound can acquire greater morphogenetic plasticity and, together with the underlying wound dermis, can engage in an embryonic-like process of hair follicle neogenesis. Future studies should uncover the cellular and signaling basis of this remarkable adult wound regeneration phenomenon.     

Modulation of gastrointestinal wound repair and inflammation by phospholipids

The mucosal surface of the digestive tract is a critical barrier between a broad spectrum of noxious and immunogenic substances present in the gastrointestinal lumen and the underlying mucosal immune system. Its preservation following various forms of injury or physiological damage is essential to prevent the invasion of harmful luminal factors into the host, which subsequently may lead to inflammation, uncontrolled immune response, and a disequilibrium of the homeostasis of the host. The preservation of this barrier following injuries is regulated by a broad spectrum of structurally distinct regulatory molecules, including phospholipids. Phospholipids play a pivotal role in the modulation of intestinal inflammation. They have been demonstrated to both promote and inhibit inflammation, and their overall impact in an individual setting seems to be dependent on several factors, including the level of immune cell activation and the presence of other mediators. Modulation of lipid mediators through administration of lysophosphatidic acid (LPA) or lisofylline (LSF), inhibitors of phospholipase A2 (PLA2) biosynthesis or monoclonal antibodies against thromboxane (TBX) or platelet-activating factor (PAF) as a therapeutic approach have been used in several models of inflammation; however, beneficial effects were not always convincing and further studies are warranted.     

New insights in wound response and repair of epithelium

Epithelial wounds usually heal relatively quickly, but repair may be impaired by environmental stressors, such as hypoxic or diabetic states, rendering patients vulnerable to a number of corneal pathologies. Though this response appears simple, at first, years of research have uncovered the complicated biochemical pathways coordinating the wound healing response. Here, we investigate signaling cascades and individual proteins involved in the corneal epithelium's self‐repair. We will explore how an epithelial cell migrates across the wound bed and attaches itself to its new post‐injury surroundings, including its neighboring cells and the basement membrane, through focal adhesions and hemidesmosomes. We will also discuss how the cell coordinates this motion physiologically, through calcium signaling and protein phosphorylation, focusing on the communication through purinergic, glutamatergic, and growth factor receptors. Many of these aspects reflect and can be extended to similar epithelial surfaces, and can be used to facilitate wound healing in patients with various underlying pathologies. The collective library of laboratory and clinical research done around the world has demonstrated how important precise regulation of these processes is in order for the injured corneal epithelium to properly heal. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.     

OxymiRs in cutaneous development,wound repair and regeneration

The state of tissue oxygenation is widely recognized as a major microenvironmental cue that is known to regulate the expression of coding genes. Recent works have extended that knowledge to demonstrate that the state of tissue oxygenation may potently regulate the expression of microRNAs (miRs). Collectively, such miRs that are implicated in defining biological outcomes in response to a change in the state of tissue oxygenation may be referred to as oxymiRs. Broadly, oxymiRs may be categorized into three groups: (A) the existence (expression and/or turnover) of which is directly influenced by changes in the state of tissue oxygenation; (B) the existence of which is indirectly (e.g. oxygen-sensitive proteins, metabolites, pH, etc.) influenced by changes in the state of tissue oxygenation; and (C) those that modify biological outcomes to changes in the state of tissue oxygenation by targeting oxygen sensing pathways. This work represents the first review of how oxymiRs may regulate development, repair and regeneration. Currently known oxymiRs may affect the functioning of a large number of coding genes which have hitherto fore never been linked to oxygen sensing. Many of such target genes have been validated and that number is steadily growing. Taken together, our understanding of oxymiRs has vastly expanded the implications of changes in the state of tissue oxygenation. This emerging paradigm has major implications in untangling the complexities underlying diseases associated with ischemia and related hypoxic insult such as chronic wounds.