Healing and Repair: an Overview

Hi :) In this post we’ll take a look at the general process of healing and repair. I’ll explain the elements of the healing process and how these influence the healing of a tissue. I’ll also give an overview of the healing process. Enjoy!

The aim of inflammation in the body is ultimately to restore the original structure and function of the affected tissue. This is known as complete regeneration. However, this isn’t always possible and so a compromise, that is repair, is reached. Tissue regeneration and repair are parts of the healing process which is in continuum with inflammation. ‘Regeneration’ refers to the restoration of cells identical to those that are lost. ‘Repair’ refers to variable amounts of regeneration and tissue replacement by connective scar tissue.
When a tissue or organ is injured there are three possible outcomes. The animal can become overwhelmed by the injury and die; it can cope well, initiate an acute inflammatory response and recover completely through regeneration or repair; or the animal can cope poorly with the injury and the inflammation becomes chronic. 

The Elements of the Healing Process

There are four factors that determine whether a tissue will regenerate or repair: cellular factors, chemical mediators, stromal factors, and additional factors.

Cellular Factors

Tissue Specific

In regards to the tissues, there are two factors that affect the ability of its cells to regenerate. This is the inherent nature of the cells and their relationship with their scaffold and blood supply.

Nature of the Cells

 The cells of a tissue can be grouped according to their potential to proliferate. Labile cells are present in one of the active phases of the cell cycle and have a rapid turnover and so surviving labile cells are able to proliferate and restore the lost tissue. Examples of labile cells are most epithelial cells and haematopoietic cells.

The second group of cells is the stable cells. These are present in the resting phase of the cell cycle and can be recruited to enter the cell cycle by exposure to growth factors or changes in the extracellular matrix. They have a slow cell turnover but surviving cells are also able to proliferate and restore the tissue that has been lost. Examples include mesenchymal and parenchymal cells.   

The third group of cells is the permanent cells. These are non-replicative cells as they have left the cell cycle and aren’t able to be recruited back into the cell cycle. Thus they can’t regenerate lost tissue. Examples include cardiac myocytes, and neurons in skeletal muscle. 

Tissue Non-Specific

These factors include cells that are found all around the body and are common in different types of tissues.

Macrophages

Macrophages are important in the acute inflammatory response and this has been explained in previous posts. In addition to this function, they are essential to the progression of chronic inflammation as well as the transition from inflammation to healing. Macrophages remove dead cells and matrix through phagocytosis and are an important source of growth factors that are needed for healing.

Fibroblasts

Fibroblasts are the main cell type in connective tissue and are stable cells that maintain the capacity for rapid growth. These cells are important in repair because they proliferate locally and synthesise extracellular components to provide structural integrity and tensile strength in wounds. They are produce growth factors. Fibroblasts are heterogeneous and some become contractile cells (known as myofibroblasts) and play a critical role in wound contraction.

Endothelial Cells

 The endothelial cells respond quickly to growth factors released by macrophages and proliferate in order to restore blood supply to the damaged tissue. The endothelial cells are also an important source of growth factors too. In addition, newly formed blood vessels are leaky which causes fluid similar in composition to plasma as well as inflammatory cells to be released in the surrounding tissue. This provides the cells involved in the healing and repair process a source of nutrients, proteins and cells important in the immune response.

Chemical Mediators: Growth Factors

 Growth factors have a few functions in regards to cellular repair and regeneration including initiation of cellular proliferation and the stimulation of cellular movement, contractility, differentiation and angiogenesis. Some of the important growth factors include:

-          EGF (Epidermal Growth Factor), TGF-a (Transforming growth factor), and HGF (hepatocyte growth factor): these are important for epithelial cell proliferation.

-          VEGF (Vascular Endothelial Growth Factor): for vascular proliferation

-          PGDF (Platelet Derived Growth Factor): for migration and proliferation of mesenchymal cells.

-          TGF –b: a growth inhibitor from epithelial cells and leukocytes.

-          Cytokines.

Growth factors work through a process called “receptor mediated signal transduction” which is when the growth factor binds to receptors on the surfaces of cells which causes the transcription of genes which are important in regulating the cell cycle. Growth factors can be autocrine (working on the cell that released them), paracrine (affects adjacent cells), or endocrine (travels in the blood to work on distant cells).

Stromal Factors: Extracellular Matrix

 

The interaction between tissue cells and the extracellular matrix (ECM) determines whether the cells can adhere, migrate and proliferate. There are two components to the ECM: the interstitial matrix and the basement membrane.

The interstitial matrix lies between epithelial, endothelial and smooth muscle cells. It is composed of collagen, elastin, fibronectin, proteoglycans and hyaluronate. The basement membrane is the junction between the cells and the matrix and is produced by epithelial and mesenchymal cells.

The ECM is composed of fibrous structural proteins, such as collagen and elastin, as well as cell adhesion proteins. Cell adhesion proteins include adhesion molecules on the surfaces of cells and adhesion molecules on the matrix. The interaction between these two groups of molecules determines cell growth, motility, differentiation and protein synthesis.

Additional Factors

There are several factors that may affect the healing and repair process. This includes:

-          Continued tissue damage by the original agent or a secondary agent (such as bacterial infections and foreign bodies.

-          Poor nutrition: especially protein and vitamins A and C as well as zinc

-          Poor blood supply in the area

-          Metabolic disturbances: diabetes or hyperadrenocorticism

-          Low temperatures

-          Low immune status

-          Mechanical factors.

 The Healing Process

Overview

 In general, the healing process begins within minutes to hours of the tissue being damaged and is a continuum with inflammation. Fibrin forms within the damaged tissue and this provides a “glue” to hold the tissue together. Fibrin also acts as a scaffold for the inflammatory response and fibrin degradation products as well as oedema activate tissue fibroblasts which initiates the repair process.

The healing process tries to restore the integrity, structure and function of the tissue. This process can be broken down into 5 stages:

1.       Acute Inflammation

2.       Regeneration of Parenchymal cells

3.       Migration and proliferation of parenchymal and stromal cells

4.       Synthesis of ECM proteins

5.       Remodelling of stroma and parenchymal elements

6.       Collagenisation and acquisition of wound strength.

If the cells within the tissue are labile or stable, the survivors and stem cells are able to proliferate to restore the lost tissue. As explained earlier, this is impossible in permanent cells. If the labile cells are destroyed but the stroma is intact, rapid regeneration occurs. However, if there is no intact stroma, there will be no regeneration and the tissue will die and be replaced by repair tissue.

At first, there is controlled proliferation of blood vessels and fibroblasts at the site of injury and this acts as a temporary scaffold. This tissue is called ‘granulation tissue’ and is the beginning of the formation of scar tissue.  In most cases, the granulation tissue is replaced by less specialised fibroblastic cells which fill the area with collagen, forming scar tissue. Some fibroblasts have a myofibrillar ability and this may cause contraction of the tissues.

The formation of granulation tissue has four steps:

1.       Formation of new blood vessels (angiogenesis): The basement membrane is broken down and capillary sprouts form. Endothelial cells migrate towards the angiogenic stimulus. Here they proliferate behind the tip of the sprout. Support cells then migrate and surround the newly formed tubes.

2.       Migration and proliferation of fibroblasts: the presence of fibrin in the ECM provides extra stroma for the fibroblasts and endothelial cells to migrate.

3.       Deposition of ECM: fibrillar collagen is deposited by fibroblasts

4.       Maturation and Organisation of Fibrous Tissue (Remodelling): Some factors that cause the production of collagen also activate collagenases, which degrade collagen. A balance between synthesis and degradation results in the remodelling of the collagen framework.

That’s all for now :) In the next post we’ll take a look at how healing in different organs occurs. If you have any questions please feel free to let me know.