How does the Skin Heal Wounds?

Wounds are an unavoidable part of our life. Some heal fast, some take time, some leave scars behind. An organ in the human body with the inherent ability to heal itself is the skin. How does the skin do this?

Do you know someone who has never been injured? No? Here’s a simpler question — do you remember how many times you’ve had a cut or a wound? Doesn’t it seem unlikely that anyone would answer these questions with a yes?!
 
 In medical terms, a wound is defined as an injury to the body that involves the breaking of a protective membrane (such as the skin) and damage to underlying tissues. Cuts and wounds are an everyday occurrence, which left unchecked can reduce tissue integrity, resulting in loss of function and compromised survival.
Millions of years of evolution have equipped our bodies with self-healing mechanisms. This is why we rarely worry about minor injuries. Even the medical care of major wounds (like those from burns or accidents) has historically focused on the development of techniques that supplement the body’s built-in healing mechanisms (see Box 1). To do this, we are constantly attempting to uncover the specific cells and molecular factors involved in these mechanisms. One organ that has been studied most extensively in this regard is the skin.
 
The human skin
 
As the largest organ of the body in terms of its surface area and weight, the skin acts as a protective barrier against pathogens, dehydration, chemical toxins, and harmful UV rays. With its immense regenerative potential, the wound repair capacity of the skin is among the highest of all the organs in the body, exceeding even that of the heart (after a heart attack) and the brain (after a stroke).
 
Mammalian skin is composed of three layers (see Fig. 1):
 
Fig. 1. The three layers of human skin.
 
Credits: CNX OpenStax, Wikimedia Commons. URL: https://commons.wikimedia.org/wiki/File:OSC_Microbio_17_02_Skin.jpg. License: CC-BY.
 
The epidermis: is the visible portion of the skin. It consists of cells called keratinocytes, which are organized into different sub-layers. Epidermal stem cells in the innermost sub-layer divide to populate other layers. As the dividing cells mature, they get pushed upwards to replace worn out/damaged cells on the surface. The  epidermis also consists of hair follicles, sweat glands, and sebaceous glands.
 
The dermis: forms the support structure below the epidermis. It mostly contains cells called fibroblasts, which produce the extracellular matrix (ECM). Most blood vessels and nerves lie in this layer and have extensions connecting them to cells in the epidermis.
 
The hypodermis: is made up of adipose or fat tissue. Its presence is vital in providing insulation to the body.
 

Cells populating all three skin layers drive the healing process. In addition, the skin has some immune cells, like macrophages and mast cells, which are capable of an immediate response to injury or infection (see Box 2).

Wound healing in the skin

The healing process occurs in four phases over a period ranging from seconds to months (see Fig. 2).

Fig. 2. Stages of wound healing.

Credits: OpenStax College, Wikimedia Commons. URL: https://commons.wikimedia.org/wiki/File:417_Tissue_Repair.jpg. License: CC-BY.

(a) Hemostasis

The first step in wound healing involves the formation of a clot to limit the loss of blood. A clot is formed by the coordinated activity of many cells and tissues — each of which receives information on when and how to act through multiple signaling events. In intact blood vessels, endothelial cells (which form the inner lining of blood vessels) release chemicals (like prostacyclin) to prevent the accumulation of platelets and ensure smooth blood flow. When wounding results in damage to blood vessels, this inhibition is no longer effective and platelets quickly accumulate at the site of injury. These platelets secrete copious amounts of a fiber-like protein, called fibrin, that interconnect to form an insoluble mesh (clot) at the wound site, thereby sealing it. Hemostasis typically occurs within a few seconds to a few minutes.

Simultaneously, wound healing is initiated by the release of chemical triggers from a variety of sources. Healthy neighboring cells are informed of the injury through two kinds of molecular signals. One signal consists of molecular motifs, called Damage Associated Molecular Patterns (DAMPs), which are characteristic of the cellular debris (like, DNA, RNA, proteins) of dead and damaged body cells at the wound site. The other consists of molecular motifs, called Pathogen Associated Molecular Patterns (PAMPs), that are typical of metabolites of resident and pathogenic bacteria (like membrane lipopolysaccharides, peptidoglycans etc.) that invade the body through an open wound. On recognizing these DAMPs and/or PAMPs, a cascade of chemical events is activated in healthy neighbouring cells. This cascade results in the secretion of chemicals that attract immune cells (like macrophages) to the wound site. Recent studies suggest that a release in cellular tension (because of the loss of cell-cell bonding in the damaged tissues) can also act as a trigger for the initiation of wound healing.

The platelets that form the clot at the wound site also trigger healing by releasing chemical signals, such as platelet derived growth factor (PDGF). Cells of the immune system (like macrophages, monocytes, neutrophils) and connective tissue (like fibroblasts) recognize these chemical signals and migrate towards the wound site. These infiltrating immune cells perform two roles — they fight infectious pathogens that enter the body through this breach in its barrier, and remove debris accumulated in the form of dead cells.
 
(b) Inflammation
 
Inflammation can be described as a local response of the immune system to injury. In the 1st century AD, Aulus Celsus (a Roman encyclopaedist, known for his extensive work in the field of medicine) described the four fundamental signs of inflammation — calor (heat), dolor (pain), rubor (redness) and tumor (swelling). Even today, early phases of healing are characterized by these signs.
 
Inflammation of the skin usually appears within a few hours of the injury and may persist for a period ranging from a few (2-4) days to a couple of weeks. Damaged skin cells secrete cellular chemicals, which induce healthy cells in the vicinity to proliferate and migrate to the site of injury. Some of these chemicals diffuse into surrounding tissue, attracting and activating immune cells in the skin and blood vessels. For e.g., mast cells and basophils release histamine (a cellular signaling molecule, often the cause of itching during an allergic response) that causes blood vessels to dilate and become more permeable. This promotes the leakage of various immune cells and plasma proteins (like albumin and antibodies) from blood into the damaged tissue.
Immune cells enter the wound site in phases, forming an army to fight off any microbial invaders along its borders. The first cells to do this are components of the innate immune system. For e.g., macrophages and neutrophils help clean-up debris from pathogens and body cells. Macrophages also secrete cytokines to attract dermal fibroblasts to the wound site (see Box 3). These cytokines help form new blood vessels in a process called angiogenesis to replace damaged ones. The innate immune response is followed by an adaptive one involving the T and B lymphocytes. In addition, all the immune cells at the wound site secrete chemical signals (factors) that activate epidermal keratinocytes, dermal fibroblasts, and skin stem cells (which lie in hair follicles as well as other parts of the epidermis). Cross talk, through chemical signaling, between resident and infiltrating cells (immune cells, keratinocytes, fibroblasts, and stem cells) at the wound site leads to the next phase of the healing program.
 
(c) Proliferation
 
Once activated, fibroblasts proliferate and migrate towards the wound site, where they secrete components of the ECM. The ECM includes proteins like collagen, fibronectin and other compounds that are necessary to form a supporting structure for the closure of the wound. Because of their ability to extend and retract,  myofibroblasts (also known as activated fibroblasts) mediate contraction of the wound area through a process involving communication with the ECM. 
 
The immune cells and fibroblasts secrete cytokines that activate epidermal stem cells. These factors include transforming growth factor (TGF-β), keratinocyte growth factor (KGF), and epidermal growth factor (EGF). Once activated, epidermal and hair follicle stem cells proliferate and migrate towards and over the newly formed ECM scaffold to seal the wound. This process, known as reepithelialization, culminates in wound-closure.
 
The lack of oxygen at the injury site triggers resident cells to release chemical signals to initiate angiogenesis. Macrophages and fibroblasts are known to promote this process by releasing chemicals like lactic acid, biogenic amines, fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF). This process is a  prerequisite for renewed oxygen supply to the newly formed tissue.
 
(d) Remodeling
 
The activation of fibroblasts during the proliferative phase results in the deposition of excessive amounts of ECM proteins (e.g., collagen) in the skin. This is responsible for the formation of scars. Severe wounding leads to the activation of a greater number of fibroblasts, resulting in scars that are much deeper and stay for much longer. 
 
One hallmark of this phase is the activation of protein degrading enzymes, like the Matrix Metalloproteinases (MMPs). MMPs chew up excessive ECM proteins, making space for growing blood vessels and newly formed cells. The action of this enzyme is apparent in the fading of scar tissue, a process that can take anywhere between a few months to many years to accomplish, depending on the severity of the wound. For e.g., you may have observed the scar from a paper cut disappearing in a few days, while that from a deeper wound (e.g., from a fall on the road) taking months or years to completely vanish.
 
To conclude
 
Today, we have more than 5000 products to aid wound healing, and the future holds immense promise. Wounddressing material with the capacity for sustained release of various growth factors (chemicals that stimulate cell division and migration) and disinfectants (antiseptic chemicals to avoid infection) are currently under development to enhance the wound healing process. 
Fig. 3. Wound healing is not an error-free process.
 
Credits: Tanay Bhatt, Gaurav Kansagara, Neha Pincha & Colin Jamora. License: CC-BY.Tissue_Repair.jpg.
License: CC-BY.
 
Wound healing is, however, not an error-free process (see Fig. 3). In some cases, healing is not initiated because some cellular actors are unresponsive to wound signals. One example of this is seen in non-healing diabetic ulcers — high blood sugar interferes with both the immune response and the potential of skin cells to proliferate and migrate. Wound healing can also be delayed with age because of the reduced production of growth factors at the wound site. Both cases are treated by providing growth factors that mimic the natural wound-response of cells. This kick-starts the healing program and helps in reepithelialization.
 
In a healthy body, as a wound heals, the cells that collect at the site of injury return to their normal functions (homeostasis). However, in some cases, the wound-healing response continues even when not needed. Research reveals that severe scar formation can hinder the ability of the wounded tissue to function normally (see Box 4). In such cases, excessive secretion of collagen from hyperactive fibroblasts results in the development of a pathological condition called fibrosis. Fibrosis can occur in connective tissues of various organs in our body, such as the heart, liver, kidneys, lungs etc. This condition leads to loss of structure and function of the organ involved. In severe cases, it can even lead to death. Skin fibrosis is manifested in several forms such as keloids, scleroderma, and various types of skin cancers.
 
Interestingly, the proteins and processes (like increased inflammation, angiogenesis, and fibroblast activation) that are central to the wound healing process are found to be exaggerated in certain classes of cancer. This discovery has led to the popular hypothesis that describes cancer as an over-healing wound. Parallel research on wound-healing and cancer may hold the potential to open up new therapeutic targets for both.
 
 

Tanay Bhatt is pursuing a PhD at the Institute for Stem Cell Science and Regenerative Medicine (inStem), Bengaluru under the guidance of Prof. Colin Jamora. He studies triggers that initiate the skin healing process. He can be contacted at tanaybhatt123@gmail.com.

Gaurav Kansagara is a graduate student at the Jamora lab at inStem. He is investigating the regulation of fibroblast activation in wound-healing and skin fibrosis. He can be reached at gauravk.ncbs@gmail.com.

Neha Pincha is currently pursuing post-doctoral research at UCSF, USA. She completed her PhD under the supervision of Colin Jamora at inStem, where she discovered novel mechanisms by which mast cells contribute to the development of skin fibrosis. She can be contacted at npincha@gmail.com.

Colin Jamora is a professor at inStem, Bengaluru. He is the coordinator of the Centre for Inflammation and Tissue Homeostasis. His lab works on elucidating the mechanisms that underlie the wound-healing response, and the diseases that arise when this healing program malfunctions. He can be contacted at colinj@instem.res.in.

 

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