Are Cells That Form Fibrils And Are Active In The Repair Of Injury
Organogenesis. 2010 Oct-Dec; half-dozen(iv): 225–233.
Tissue repair
The subconscious drama
Received 2010 May ane; Accepted 2010 Jun 1.
Abstract
Equally living beings that come across every kind of traumatic result from paper cut to myocardial infarction, we must possess ways to heal damaged tissues. While some animals are able to regrow complete body parts following injury (such as the earthworm who grows a new head following bisection), humans are sadly incapable of such feats. Our ways of recovery post-obit tissue impairment consists largely of repair rather than pure regeneration. Thousands of times in our lives, a meticulously scripted just unseen wound healing drama plays, with cells serving as actors, extracellular matrix as the setting and growth factors equally the means of advice. This commodity briefly reviews the cells involved in tissue repair, their signaling and proliferation mechanisms and the function of the extracellular matrix, then presents the actors and script for the three acts of the tissue repair drama.
Key words: tissue repair, regeneration, scarring, wound healing, growth factors, extracellular matrix, stem cells
Proem
All the world'south a phase,
And all the men and women but players;
They have their exits and their entrances
And one human in his fourth dimension plays many parts,
His acts being vii ages
Shakespeare
As You Like It
Deed two, scene vii, 139–143
The term "repair," when used in the context of the healing of damaged tissue, is defined as the restoration of tissue architecture and function subsequently an injury. It encompasses ii separate processes: regeneration and replacement. Regeneration refers to a type of healing in which new growth completely restores portions of damaged tissue to their normal country. Replacement refers to a type of healing in which severely damaged or non-regenerable tissues are repaired past the laying down of connective tissue, a process commonly referred to as scarring. While a few types of tissue injury (such every bit pocket-size newspaper cuts) can sometimes exist healed in such a way that no permanent harm remains, most of our tissue repair consists of both regeneration and replacement. Tissue repair may restore some of the original structures of the damaged tissue (such as epithelial layers), simply may also result in structural abnormalities that impair organ function (such as the scar formed in the healing of a myocardial infarction).
Whether the healing of a wound proceeds downward the regeneration or the replacement pathway (or both) depends, in role, on the blazon of tissue in which it occurs. Sure tissues of the torso are more capable of cellular proliferation (and hence regeneration) than others. In this regard, at that place are three types of tissues: continuously dividing tissues, quiescent tissues and nondividing tissues. Continuously dividing tissues (too known as labile tissues) are comprised of cells that are constantly proliferating in club to supersede expressionless or sloughed-off cells. Examples of such tissues include epithelia (such as skin, gastrointestinal epithelium and salivary gland tissue) and hematopoietic tissues. These tissues contain pools of stem cells, which have enormous proliferative and self-renewing ability, and which give rise to more than one blazon of jail cell. Replicating asymmetrically, each stem cell gives rise to one daughter cell that differentiates and matures and another daughter jail cell that remains undifferentiated and capable of beginning some other self-renewing cycle.
Some tissues, known as quiescent tissues (or stable tissues) are composed of cells that commonly exist in a non-dividing country only may enter the prison cell cycle in response to certain stimuli, such every bit prison cell injury. Tissues falling into this category include parenchymal cells of the liver, kidney and pancreas, mesenchymal cells such as fibroblasts and smooth muscle cells, endothelial cells and lymphocytes. Information technology should be noted that the liver, unlike other quiescent tissues, has a relatively robust proliferative capacity. When a lobe of the liver is resected for donation, for instance, the remaining liver cells proliferate at such a rate that the liver reaches a size similar to that prior to resection. While this process is normally described as regeneration, it is more accurately viewed equally compensatory growth, since the original lobe itself does not regrow. A few types of tissue are composed of cells that take left the cell cycle permanently, and are therefore unable to proliferate. These nondividing tissues (or permanent tissues) include cardiac and skeletal muscle. Tissue repair in these tissues always leaves permanent bear witness of injury, such as a scar.1
Dramatis Personae
The bandage of characters in the tissue repair drama is large and varied. Hither we list the major actors, with a focus on those that may be less known to the reader. Central in the drama are the tissue's own lost or damaged cells, which in most cases are terminally differentiated and incapable of replication. In nondividing tissues, such as myocardial tissue, lost cells are simply never replaced. In other tissues, however, replacement is possible. Continuously dividing tissues are particularly adept at cocky-renewal, undergoing innumerable cycles of jail cell loss and replacement during a normal human lifespan. The regenerative capacity of these tissues lies not in their parenchymal cells (which are terminally differentiated and thus unable to replicate), only in stem cells located deep within the tissue.
Stem cells are unique for ii reasons: (1) they take the ability to self-renew and (ii) they accept the chapters to generate more than one cell blazon. Self-renewal occurs either by symmetric replication (in which a stem cell gives rise to two daughter stem cells, equally capable of self-renewal) or asymmetric replication (in which ane daughter cell remains a cocky-renewing stalk cell and the other daughter prison cell differentiates and matures).
The chapters of a stalk cell to requite rise to multiple lineages of cells is most striking in embryonic stalk cells. These cells, which are denoted as pluripotent, are capable of generating cells from any of the tissues of the body. Adult (or somatic) stem cells are designated as multipotent, and give ascension to a more restricted array of jail cell types. As expected, somatic stem cells have been found in continuously dividing tissues, such every bit skin, gastrointestinal epithelial lining, cornea and hematopoietic tissue. However, they accept too been discovered in sure quiescent tissues, such equally liver, pancreas and adipose tissue, in which they do not normally produce differentiated cells. Almost surprising is the recent discovery of stem cells residing in sure parts of the central nervous system, an organ system whose tissues have long been thought to be incapable of proliferating.2
Most somatic stem cells are located in niches, micro-environments within a tissue comprised of both stalk cells and non-stem cells. Neighboring non-stem cells signal the stalk cell to divide when necessary, a task that the stem jail cell generally performs very slowly. In the peel, stem cells located in a niche inside the pilus follicle burl requite rise to all the cells comprising the pilus follicle and contribute to the production of new surface epithelial cells after wounding.iii Stem cells of the pocket-size intestine are located within monoclonal, stem cell-derived crypts that are completely regenerated every 3 to 5 days. The bone marrow contains not only hematopoietic stalk cells, which requite ascent to all blood cell lineages, just also multipotent stromal stalk cells, which travel to unlike regions in the body and generate chondrocytes, osteoblasts, adipocytes, myoblasts and endothelial cells. These stromal stalk cells participate in cell replenishment after tissue injury, but they do not seem to accept a function in normal tissue homeostasis.
Beyond the stem prison cell, 3 other types of cells are critical to the process of tissue repair: fibroblasts, endothelial cells and macrophages. In nigh wounds, complete replacement of wounded tissue to its original, unharmed state is impossible. The wound must therefore be healed using externally obtained cloth to reconnect the viable tissue margins. This process, discussed in particular later, involves the laying down of acellular fibrous tissue to replace the region of lost cells. The fibrous tissue is laid downwardly past fibroblasts, which migrate to the injured area, proliferate and secrete collagen under the influence of numerous growth factors and cytokines. In the earliest stages of wound healing, fibroblasts are few and far between, suspended together with tenuous new blood vessels in an edematous pinkish substance termed granulation tissue. Initially the new blood vessels are disquisitional in the ship of nutrients and cells to the new tissue, but later a time, they recede along with the fibroblasts, leaving a collagenous scar that is remodeled and strengthened over time. Macrophages are essential directors of this drama, secreting growth factors that entice and stimulate fibroblasts, endothelial precursor cells and (in skin wounds) keratinocytes. They as well oversee the deposition and remodeling of extracellular matrix textile.
The Script
The script of the tissue factor drama—the migration and proliferation of cells, the laying down of extracellular matrix, and the remodeling of collagen to course a durable scar—is carried out by a process known every bit receptor-mediated signal transduction. Alike to the words spoken between people, ligands such as growth factors and cytokines float between cells, carrying directives to perform a sure activeness. Cells "hear" these words when the ligands demark to jail cell-surface receptors, which bring the message into the cell, resulting in a new activity, such as migration, proliferation or secretion of a substance. Herein we will discuss the words spoken betwixt the actors, the way the actors hear these words and the manner in which the bulletin gets to the prison cell nucleus in club to outcome change.
Growth factors and cytokines.
Growth factors are specialized polypeptide molecules that bind to receptors on target cells and deliver messages regarding migration, proliferation, differentiation, survival and secretion. The list of growth factors and their attendant functions is and so long that it would revenue enhancement even the most capable memorizer. Herein we limit our discussion to the primary growth factors associated with each stage of tissue repair ( Tabular array 1 ).
Tabular array one
Major steps in wound healing and their associated growth factors
| EGF | FGF | KGF | PDGF | TGF-α | TGF-β | TNF | VEGF | |
| Fibroblast migration | Ten | X | Ten | |||||
| Fibroblast proliferation | X | X | X | X | X | |||
| Monocyte migration | X | X | 10 | 10 | ||||
| Macrophage activation | X | |||||||
| Epithelial migration | 10 | X | X | Ten | ||||
| Epithelial proliferation | X | X | X | X | ||||
| Angiogenesis | X | X | Ten | 10 | X | |||
| Collagen synthesis | 10 | X | ||||||
| Collagenase synthesis | X | 10 | X | Ten | Ten | |||
| Wound wrinkle | X | X |
EGF, epidermal growth cistron; FGF, fibroblast growth factor; KGF, keratinocyte growth cistron; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
Ane of the most critical growth factors in tissue repair is transforming growth factor beta (TGF-β). This growth factor belongs to a superfamily that also includes a number of other factors with wide-ranging functions, such every bit bone morphogenetic proteins, activins, inhibins and Müllerian inhibiting substance.4 Made by platelets, endothelial cells, lymphocytes and macrophages, TGF-β binds to cell-surface receptors that accept serine/threonine kinase activity, triggering phosphorylation of cytoplasmic transcription factors called Smads, so-named for the two drosophilia proteins of which they are homologs: the mothers against decapentaplegic (MAD) and Caenorhabeitis elegans proteins.5 Smads then enter the nucleus and affect gene transcription.
Although TGF-β has many functions, its near of import office in tissue repair is to promote fibrosis, a feat it accomplishes by: (1) attracting fibroblasts and stimulating them to proliferate, (2) triggering fibroblasts to secrete collagen and (3) inhibiting extracellular matrix deposition past metalloproteinases. Not surprisingly, TGF-β is a fundamental factor in conditions involving pathologic fibrosis, such every bit pulmonary fibrosis, systemic sclerosis and Marfan syndrome.6 In addition to its fibrogenic effects, TGF-β besides inhibits epithelial cell growth, diminishes inflammation and promotes invasion and metastasis in tumors.7
Another essential, multitasking growth cistron is platelet-derived growth cistron (PDGF), and then named because it is stored in platelet granules and released upon platelet activation. Made by a number of cells including macrophages, endothelial cells and shine muscle cells, PDGF is involved in about every aspect of tissue repair. Information technology calls neutrophils, macrophages and fibroblasts to the wound expanse and subsequently stimulates and activates them. It also induces angiogenesis, triggers product of matrix metalloproteinases (MMPs), fibronectin and hyaluronic acrid and aids in wound contraction.eight
Fibroblast growth gene (FGF) calls virtually all of the major players (macrophages, fibroblasts and endothelial cells) to the scene of the wound. It initiates the migration of epithelial cells in from the margins of the wound, mediates wound contraction and stimulates angiogenesis.ix Contrary to what one might infer from its proper name, however, FGF does not stimulate collagen synthesis. The more than accordingly-named vascular endothelial growth factor (VEGF) acts primarily on endothelial cells. Information technology is a potent inducer of blood vessel formation in tissue repair likewise as in early fetal development.10 Overexpressed in certain tumors, peculiarly renal cell carcinoma, VEGF is a target for the development of new chemotherapeutic agents.eleven Other growth factors include epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Both stimulate epithelial cell and hepatocyte proliferation and raise epithelial cell migration. Once known equally the scatter cistron, HGF also promotes jail cell scattering during embryonic development.12
In improver to growth factors, cytokines also carry important messages between cells during tissue repair. Pocket-size proteins secreted past cells of the immune system, cytokines are perhaps best known for their role as immunomodulators within both the cellular and humoral artillery of the adaptive immune system. Three cytokines in particular are involved in tissue repair: tumor necrosis factor (TNF) and interleukin-1 (IL-1) participate in the wound healing phase of tissue repair and TNF and interleukin-6 (IL-half dozen) are involved in liver regeneration.13
Receptor-mediated signaling.
For humans, words must be seen or heard to take pregnant. So information technology is with the messages between cells in the tissue repair drama: the growth cistron or cytokine message must accept a way to get into the target cell for action to have place. This process is termed receptor-mediated signal transduction and information technology involves binding of a ligand (a growth receptor or cytokine) to a receptor molecule on a target cell. This binding triggers events that transduce the signal from the exterior of the prison cell to the inside. The end result is a modify in gene expression, for instance, transcription of genes that normally may be silent, such as those that control cell cycle entry.
Receptor-mediated signaling often occurs betwixt cells adjacent to one another (paracrine signaling); for instance, macrophages produce growth factors that bind to receptors on adjacent fibroblasts. Nevertheless, signaling tin can also occur between cells located at some altitude from each other (endocrine signaling), as is often the instance with cytokines and their distant targets. Signaling may fifty-fifty occur within the aforementioned cell (autocrine signaling), as when a tumor prison cell overproduces both a growth cistron and its receptor, which interact and pb to unbridled cell growth.
Whatever the way of signaling may be, at that place are 4 principal types of receptors: those with intrinsic tyrosine kinase activity, those without intrinsic tyrosine kinase action, G protein-coupled receptors and steroid hormone receptors. Receptors with intrinsic tyrosine kinase action are mutual targets for growth factors. When a growth factor binds to this type of receptor, the receptor dimerizes, causing phosphorylation of tyrosine residues and activation of the receptor. The activated receptor in turn phosphorylates other molecules, inducing them to conduct the message (or "signal") into the nucleus, resulting in a change of gene expression. Examples of deportment mediated by this type of receptor include: product of growth factors, production of growth factor receptors, production of proteins that control entry of the cell into the cell wheel and activation of cell proliferation and survival (through inhibition of apoptosis).xiv
Receptors lacking intrinsic tyrosine kinase activity use a similar phosphorylation-activation system to transmit messages into the cell; however, since they lack phosphorylating adequacy, they must recruit a carve up kinase system, called the JAK-STAT pathway, to consummate the job. The receptor transmits the indicate from the ligand (often a cytokine) on the surface of the jail cell to a Janus kinase (JAK) poly peptide inside the prison cell. Once activated, the JAK protein in turn phosphorylates and activates cytoplasmic transcription factors called STATs (point transducer and activator of transcription). Every bit their proper noun implies, STATs transduce the indicate from the JAK protein to the nucleus of the jail cell, where they actuate the transcription of certain genes.15
The largest family of signal transduction prison cell membrane receptors is comprised of One thousand protein-coupled receptors. Many different types of ligands bind to this type of receptor, such as chemokines, vasopressin, serotonin, histamine, epinephrine, norepinephrine, calcitonin, glucagon, parathyroid hormone, corticotropin and rhodopsin.xvi When the receptor receives a bespeak from a ligand, its seven transmembrane alpha helices alter conformation, allowing it to interact with a G protein. Once activated, the G protein transmits the signal to a 2nd messenger molecule, such as 3′, 5′ cyclic adenosine monophosphate (cAMP), which carries the signal to the nucleus of the prison cell. Such campsite-mediated pathways are involved in vision and olfactory sensing. Steroid hormone receptors are unique in that they are located inside the cell rather than on the cell membrane. Their ligands, which include steroid hormones, thyroid hormone, vitamin D and retinoids, must lengthened through the jail cell membrane in gild to bind to the receptor, which binds to Dna and alters gene expression.
The cell bicycle.
1 of the principal actions in the tissue repair script is cell proliferation. In order to heal later on injury—whether past regeneration or scarring—cells must enter and progress through the cell bicycle, a tightly-regulated procedure that consists of ii main activities: DNA replication and mitosis. Continuously proliferating cells are always moving through the jail cell cycle, whereas quiescent cells must be called into the cell cycle by growth factors or cytokines (via receptor-mediated point transduction) or past ECM components (via integrins).
The cycle consists of iv sequent phases: the G1 (presynthetic) phase, the S (Dna synthesis) phase, the Yard2 (premitotic) stage and the M (mitotic) phase. Cells may begin their journeying through the bicycle from G1 or G0 (a resting phase outside the cell bike). In social club to move from M0 to G1, cells must activate numerous previously-silent genes including proto-oncogenes, genes required for ribosome synthesis and genes required for protein translation. To move into the South phase and begin the process of replication, cells must laissez passer a checkpoint at the stop of G1. Several such checkpoints congenital into the cycle operate as quality-control monitors, validating that the cell has accurately completed i stage of the cell bicycle before assuasive the cell to progress to the next phase. The M1 checkpoint assesses the integrity of DNA before allowing cells to pass through to Due south phase. It too serves equally a decision bespeak, determining whether the prison cell should divide immediately, carve up at a later bespeak or enter a resting stage. Another checkpoint at the finish of Gii evaluates DNA after replication to see if the cell can safely enter mitosis. A separate metaphase checkpoint monitors the alignment of chromosomes at the mitotic plate and when alignment is achieved, allows chromosomes to divide into their sis chromatids. After splitting into 2 daughter cells, the cell once more enters Thou1.
Considering the correct functioning of the cell bike is crucial to its integrity, at that place are multiple controls built into the system, including activators, inhibitors and sensors that command checkpoints in the cycle. Proteins called cyclins, together with associated cyclin-dependent poly peptide kinases (CDKs), bulldoze the cell cycle by phosphorylating proteins that are essential for jail cell wheel transitions.17 One such poly peptide is the retinoblastoma (RB) poly peptide, which in its normal, unphosphorylated state stalls the cell at the Chiliad1/S transition by binding and inactivating the transcription factor E2F.18 When RB is phosphorylated past cyclins, information technology releases (and activates) E2F, allowing transcription of genes necessary for cell bike progression. Cyclin proteins are themselves regulated past CDK inhibitors.
The Stage
The stage upon which the drama unfolds is a special blazon of tissue known equally extracellular matrix (ECM). ECM exists in ii forms: interstitial matrix (a gelatinous, amorphous intercellular material) and basement membrane (a thin, highly-organized, plate-like layer upon which epithelial cells remainder). Although information technology may announced inert and static, ECM has a long listing of responsibilities and functions. Beyond its obvious physical characteristics—imparting resilience to soft tissues and firmness to bone—it likewise stores and presents growth factors, acts as a scaffold to which migrating cells tin can attach and establish polarity and facilitates prison cell growth both in physiologic and tissue repair settings. ECM is the always-changing background for regeneration and wound healing, but it also accompanies other processes such equally morphogenesis, chronic fibrotic processes and tumor invasion/metastasis.
The many constituents of the ECM can exist grouped into three types of molecules, according to their primary functions: structural molecules (such as collagen and elastin), adhesive molecules (such as integrins, fibronectin and laminin) and resilient components (such as proteoglycans and hyaluronan). The interstitial matrix is composed primarily of collagen, elastin, fibronectin, proteoglycans and hyaluronan, whereas the basement membrane is equanimous largely of nonfibrillar collagen, laminin and proteoglycans.1 A brusque description of each major ECM component follows.
Collagen, the virtually mutual poly peptide in the animal world, consists of three bondage that combine to form a triple helix trimer. Although 27 types of collagen have been identified, less than half of these have major roles in the man body. Fibrillar collagens (types I, II, 3, V and IX) are plant in many types of difficult and soft tissues. Type IV collagen, which is arranged in long sheets rather than fibrils, is a primary component of basement membranes. Collagen imparts strength to tissues, just the ability to stretch and snap dorsum into shape is provided past elastic fibers. Elastic fibers are equanimous of a central core of elastin surrounded by fibrillin, a glycoprotein that controls the availability of TGF-β within the ECM.
Adhesive molecules, such as integrins, fibronectin and laminin, provide connections between cells or between cells and ECM components. Integrins are transmembrane glycoproteins with an extracellular domain that attaches to ECM components, such equally laminin and fibronectin and an intracellular domain that links to cytoskeletal complexes.nineteen They are operative in the earliest stages of wound healing, helping leukocytes adhere to vascular endothelium in preparation for their transmigration through the vessel. Fibronectin helps stabilize the initial blood clot filling the wound by binding to fibrin; information technology likewise provides a framework for edifice the collagen matrix during wound healing. Laminin provides a connexion betwixt cells and the ECM; it also binds with type Iv collagen to grade the basement membrane.
The resilient nature of the ECM is provided past proteoglycans and hyaluronan. Both of these substances are composed of glycosaminoglycans (GAGs), long repeating polymers of disaccharides. Proteoglycans, which consist of GAGs linked to a protein core, accept many different roles: regulation of ECM permeability, arbitration of inflammatory and immune responses and control of cell growth. Hyaluronan, comprised of many repeats of a single dissacharide, binds huge amounts of water and provides strength and turgor to connective tissue.
The Drama
Preface: regeneration vs. scarring.
True regeneration, in which new cells replace damaged or expressionless cells such that the tissue is restored to its original land, occurs infrequently in humans. Two weather must be met for a tissue to undergo pure regeneration (without scarring): (1) the injured cells must exist capable of proliferation (as is the case in continuously dividing and quiescent tissues) and (2) the underlying stromal framework must be intact.
Regeneration occurs in a physiologic way in continuously dividing tissues. Sloughed-off gastrointestinal epithelial cells, for example, are replaced by new cells arising from stem cells in the intestinal crypts. Pathologic examples of pure regeneration, however, are few and far between. Ane example occurs when the liver undergoes acute, toxic injury from acetaminophen overdose. In this type of injury, hepatocytes are destroyed, simply the underlying stromal framework remains intact, allowing for the possibility of complete regeneration of the injured tissue.20
In a procedure akin to regeneration, some organs are able to abound in size in response to resection. If a lobe of the liver is resected, the remaining liver will abound larger in response. A moving ridge of replication occurs as hepatocytes are pulled from their quiescent country and enter the cell cycle. Following a second wave of replication in nonparenchymal cells (such every bit Kupffer cells and endothelial cells), hepatocytes return to their quiescent state. This process, though often termed "regeneration," is not true regeneration, but compensatory growth. True regeneration of lost organs is, at this time, a process relegated to certain animal species and science fiction movies, but peradventure in the non-and so-distant futurity stem cells will be used for this purpose.21
If an injury damages only parenchymal cells in a continuously-dividing or quiescent tissue, repair by regeneration is possible. However, if an injury is so severe as to damage not simply the parenchymal cells merely also the underlying stromal framework of the tissue (every bit occurs in most injuries) or if the injury occurs in non-dividing tissues, regeneration is impossible. In these instances, the tissue is repaired past the degradation of fibrous tissue in the defect created by the wound. Regeneration involves restitution of tissue components; repair involves "patching" rather than restoring. The amount of regeneration vs. repair that occurs depends on the proliferative chapters of the cells, the integrity of the stromal framework and the duration of the injury and inflammatory response.one
Repair by connective tissue involves the influx of debris-removing inflammatory cells, formation of granulation tissue (a substance consisting of fibroblasts and delicate capillaries in a loose extracellular matrix) and conversion of said granulation tissue into fibrous tissue that is remodeled over time to form a scar. In that location are five major components in this process: inflammation, new vessel formation, fibroblast proliferation, collagen synthesis and scar remodeling.
Though the general principles are the same no matter what blazon of wound is beingness healed, the extent of granulation tissue, inflammation and scarring vary depending on the size and type of wound. In the case of skin wounds, in that location are 2 types of wound healing: first-intention healing and 2nd-intention healing.22 Wounds healing by outset intention are relatively small, with limited epithelial and connective tissue harm, such every bit paper cuts, well-approximated surgical incisions and superficial stab wounds. Healing in this blazon of wound is generally rapid, since the area of the defect is relatively pocket-size. Inflammation and granulation tissue are present but not abundant and scarring is minimal.
In contrast, wounds healing past second intention are larger wounds with margins that are non easily approximated, such as burns, infarctions, ulcers and large excisional skin wounds. This type of wound necessarily heals more slowly, as the defect to be repaired is larger. The abundance of fibrin, necrotic debris and exudate necessitates a more than intense inflammatory response and consequently the chance of inflammation-mediated injury is greater than it is in offset-intention healing. Granulation tissue is abundant and wound contraction and scarring is maximal. Despite these differences between starting time and second intention healing, the underlying drama is very similar. Nosotros will present the drama as information technology occurs in first intention wounds, noting second intention differences where necessary.
Act I: inflammation.
Immediately later the wound is inflicted, the most urgent task is non to repair the damaged tissue, but to finish the flow of claret from the wound. Within seconds of the injury, exposed collagen activates coagulation in the region of the injury. Platelets form an initial plug, coagulation cascade factors collaborate to form fibrin (which seals and solidifies the plug) and a blood clot soon appears at the skin surface. Non only does the clot terminate the bleeding, only it serves as a scaffold for incoming cells and a repository of cytokines and growth factors.22 , 23
At the pare surface, all appears static and calm as the clot dries and forms a scab. Underneath the surface, however, a flurry of activity begins. An regular army of neutrophils rushes to the scene through dilated local blood vessels, called to the surface area by IL-i, TNF, TGF-β and other growth factors. Inside 24 hours, the neutrophils appear at the edges of the wound incision, using the fibrin scaffolding of the clot to invade the region of destruction, their primary tasks beingness to break down debris and kill bacteria.
Epithelial cells, meanwhile, brainstorm their arduous process of repair by crawling from the basal layers of the epidermis into the wounded region, depositing basement membrane components as they migrate. They are called to begin this procedure by EGF and TGF-α, secreted by activated platelets and macrophages. In addition, fibroblasts secrete KGF (keratinocyte growth factor) and IL-6, factors that heighten keratinocyte migration and proliferation.24 , 25 Fusing in the midline underneath the inert scab, these epithelial jail cell pioneers form the first thin, continuous layer of epithelium upon which the rest of the new epithelium volition exist congenital.26
Human action Ii: proliferation.
Post-obit the initial flurry of clotting and neutrophil activity, the work of jail cell proliferation begins in earnest. The characteristic characteristic of this act in the drama is the germination of a substance called granulation tissue, a pink, soft material and then-named for its irregular, grainy appearance. Consisting of new claret vessels and fibroblasts in an extracellular matrix, granulation tissue is laid down over a menstruum of a few days, offset with a few small, tenuous blood vessels and scattered fibroblasts. Initially, the new vessels are leaky and the granulation tissue has an edematous, loose appearance ( Fig. 1 ). As the vessels grow stronger and fibroblasts begin to lay down collagen, it takes on a more than substantial advent, reaching its maximum vascularity by day v.1
Pare ulcer showing early on-phase granulation tissue with numerous blood vessels and scattered fibroblasts in a loose extracellular matrix. Numerous neutrophils are present within the granulation tissue.
Macrophages—large, multitasking cells derived from monocytes— now replace the neutrophils that were so numerous in the immediate aftermath of the wounding. As their proper name suggests, a primary function of macrophages is the ingestion of unwanted materials: bacteria, cell remnants, debris, fibrin and foreign cloth. Simply macrophages too serve every bit directors for many other parts of the drama. They phone call in and stimulate fibroblasts and keratinocytes (through release of PDGF, TGF-β, TNF, IL-1 and KGF), stimulate angiogenesis (by secretion of VEGF, FGF and PDGF) and direct the laying down and remodeling of extracellular matrix [through the use of TGF-β, PDGF, tumor necrosis gene (TNF), osteopontin (OPN), IL-1, collagenase and matrix metalloproteinases (MMPs)].22
The formation of new blood vessels (angiogenesis) begins inside the first few days following injury, aided by VEGF and FGF.27 The process is unexpectedly aided by a small number of bone-marrow-derived endothelial precursor cells which habitation to the wound by mysterious mechanisms. Their contribution to the overall angiogenesis effort, yet, is minimal.28 Formation of the correct blood vessel structure is aided past integrins on the surface of endothelial cells; surrounding perithelial cells are recruited with the help of angiopoietin.
The end point toward which the entire drama is directed is the formation of a scar, a stiff collagen filler that bridges the gap left by tissue devastation, restoring strength and integrity to the tissue. This process begins with the archway of the fibroblast between days one and three, called to action by many growth factors and cytokines, including PDGF, EGF and TGF-β. At first, the blazon III collagen secreted by fibroblasts is arrayed vertically at the margins of the incision. Subsequently, the collagen combines with fibrin and plasma fibronectin (which deposition is promoted by the vascular permeability inherent in angiogenesis); this conditional matrix provides a framework for further fibroblast and endothelial cell ingrowth ( Fig. two ).29
Early granulation tissue with claret vessels in a loose matrix of collagen and fibrin.
By solar day 3 to day 5, ECM formation is well underway, with granulation tissue serving as a substrate ( Fig. 3 ). Shards of elastic tissue form within the wound site. Plump fibroblasts mature into sparse, spindle-shaped fibrocytes, which become entrapped in the dense, fibrillar collagen they accept secreted ( Fig. four ). Collagen deposition is a residue between synthesis and degradation. In these early stages, the balance tips toward collagen synthesis, aided by TGF-β, which inhibits the deposition of collagen. The process of ECM degradation ends within ii–3 weeks.
Pare ulcer showing after-stage granulation tissue with blood vessels and early collagen deposition.
Early scar germination showing fibrillar collagen, plump fibroblasts and spindle-shaped fibrocytes.
Meanwhile, the epithelium quietly continues to proliferate. Mediated by the aforementioned KGF and IL-6, information technology increases in thickness, eventually regaining its full, stratified architecture and keratinized surface some time between one and 3 weeks (or later in second-intention healing).27
Act 3: maturation.
During the second week following the incision, leukocytes gradually abandon the wound area and vessels recede ( Fig. five ). Type I collagen synthesis increases, due to both an increased number of fibroblasts and an increased rate of synthesis per fibroblast.30 Where there was once granulation tissue, in that location is now a preliminary scar, stake and business firm, equanimous of dumbo collagen, fibroblasts and shards of rubberband tissue. In some other ii weeks, even the fibroblasts brainstorm to disappear and eventually an acellular scar bridges the region of the wound, covered by intact, fully-developed epidermis. Dermal appendages in the region of the wound, still, are not reformed.
Wide excision of skin. (A) Previous punch biopsy site (center) in tardily stages of repair. (B) Dumbo, acellular, normal dermal collagen bundles (bottom) abutting new, notwithstanding-cellular fibrous tissue of the repair process (top). (C) Blood vessel in procedure of involution.
Over the next several weeks, the limerick of the extracellular matrix changes, remodeling the newly-formed scar such that it attains maximal force at an appropriate size. Although several serine protease enzymes (such as neutrophil elastase, cathepsin G, kinins and plasmin) operate in the remodeling process, the key mediators of remodeling are zinc-dependent proteases known as matrix metalloproteinases (MMPs).31 There are many different types of MMPs, including collagenases (which carve fibrillar collagen), gelatinases (which act on baggy collagen and fibronectin) and stromelysins (which degrade a number of ECM components including laminin, fibronectin, proteoglycans and amorphous collagen). MMPs are produced by many unlike types of cells, including fibroblasts and macrophages; their secretion is stimulated by PDGF and FGF and inhibited by TGF-β. In one case they are produced, MMPs are apace cleaved down past a family of enzymes known as tissue inhibitors of metalloproteinases (TIMPs). Produced by mesenchymal cells, TIMPs help reign in collagen (and other ECM component) breakdown so that scar formation tin continue.
Ultimately, strength is achieved by increased collagen synthesis, followed past post-synthetic modifications of collagen, including cantankerous-linking and increased fiber size. Early in wound healing, the collagen is relatively sparse and oriented parallel to the peel; over time, the initial collagen fibrils are resorbed and replaced with thicker fibrils aligned with stress lines.22 Wound strength increases chop-chop during the first month, then slows, reaching a plateau of 70–eighty% of the original tensile strength by the end of the tertiary month. Although total-thickness epithelial regeneration is possible, whatsoever skin appendages lost during the initial injury will not be reformed.
Given their easily-approximated margins, wounds healing by first intention generally have minimal scarring. Wounds healing by second intention, still, are larger, with more than epithelial destruction, necessitating more than collagen deposition to close the wound. The process of wound contraction eases the fibroblasts' burden a bit. Specialized contractile, smoothen-muscle-like cells called myofibroblasts appear inside the wound and pull the margins of the wound toward each other. These cells may be derived from tissue fibroblasts under the influence of FGF and PDGF; they may also develop from epithelial cells or from bone marrow precursor cells chosen fibrocytes. So efficient are these myofibroblasts that large wounds may decrease in size by up to 80%.32
When the drama ends badly.
Several systemic factors may adversely bear upon the performance of the tissue repair drama. Patients with diabetes mellitus tend to have less granulation tissue germination, less collagen degradation and defects in collagen maturation, leading to dull and ineffective wound maturation.33 While this predisposition has been attributed to the microangiopathy inherent in diabetes, contempo research indicates that other factors, such as collagen glycosylation and pericapillary albumin deposition, may play a role.22 , 34 Poor nutrition too retards the healing process. Vitamin C, in item, is necessary for collagen synthesis. Impecuniousness of this vitamin results in failure of activation of proline and lysine hydroxylases and formation of unhydroxylated procollagen peptides, resulting in an unstable, poorly cross-linked collagen helix. Conditions in which blood flow is compromised—such as cardiac insufficiency or arteriosclerosis—delay the commitment of necessary cells and factors to the scene of the wound. Certain drugs may also slow wound healing; glucocorticoids, for example, inhibit inflammation and collagen formation.
Local factors can likewise profoundly impact the quality of wound healing. The size of the wound is important (small injuries heal faster than large ones) as is the location (wounds in richly-vascularized areas of the trunk, such equally the face up, heal relatively quickly). The presence of foreign bodies may prolong healing, every bit may motion or pressure at the wound site. Nevertheless, the single most important cause of delayed healing of wounds is infection.1 If whatever beta-hemolytic Streptococcus organisms are present or if there are over 10five organisms of whatsoever bacterial species per gram of tissue, the wound will non heal.35 More common in 2d-intention healing, infection prolongs the inflammatory stage of wound healing, impeding epithelialization, collagen deposition and wound contraction. Bacterial endotoxins stimulate collagenase secretion, leading to degradation of non but the forming scar, only of surrounding normal tissue.22
On the other hand, sometimes acts in the drama are played so well, and then exuberantly, that the end result is an abnormally-healed wound. Occasionally, the balance of collagen formation and deposition tips in favor of formation, leading to hypertrophic scars or keloids. Hypertrophic scars are raised scars that remain confined to the region of the wound. They more often than not occur within 4 weeks of injury (often a astringent traumatic or thermal injury to the dermis) and may regress over time.22 , 36 An abnormal autocrine loop in which myofibroblasts produce excessive TGF-β and, hence, collagen, appears to contribute to their formation.36 Keloids are scars that accept overgrown the boundaries of the initial incision, presenting as nodules or masses of fibrous tissue ( Fig. 6 ). While keloids generally appear within ane year of the inciting injury, some may brainstorm growing years afterwards.22 For unknown reasons, keloids occur much more oftentimes in patients with darkly-pigmented pare; certain people seem to accept a predisposition towards their formation.
Keloid showing dense, haphazardly-bundled collagen bundles.
Formation of granulation tissue may as well occur in an excessive manner. In a lesion known as proud flesh, the procedure of wound healing is interrupted past masses of granulation tissue protruding above the peel surface, preventing re-epithelialization and appropriate scar germination ( Fig. 7 ).
Proud flesh with exuberant granulation tissue.
Decision
Wound healing is a carefully-scripted drama performed countless times throughout a human lifespan. Though occasionally the drama does non go as planned, in most cases impairment is contained, dead cells and tissue are removed and a scar restores integrity to the injured tissue—a triumphant performance indeed.
Abbreviations
| cAMP | 3′, v′ circadian adenosine monophosphate |
| CDK | cyclin-dependent poly peptide |
| DNA | deoxyribonucleic acid |
| ECM | extracellular matrix |
| EGF | epidermal growth factor |
| FGF | fibroblast growth factor |
| GAG | glycosaminoglycan |
| KGF | keratinocyte growth factor |
| MAD | mothers against decapentaplegic |
| MMP | matrix metalloproteinase |
| IL | interleukin |
| JAK | janus kinase |
| OPN | osteopontin |
| PDGF | platelet-derived growth cistron |
| RB | retinoblastoma |
| STAT | indicate transducer and activator of transcription |
| TGF | transforming growth factor |
| TIMP | tissue inhibitor of metalloproteinases |
| TNF | tumor necrosis factor |
| VEGF | vascular endothelial growth gene |
Footnotes
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Are Cells That Form Fibrils And Are Active In The Repair Of Injury,
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055648/
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