Session 12: Introduction to tissue healing and repair

Session 12: Introduction to tissue healing and repair

• Alex Simon (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Define tissue healing.

Identify tissue healing processes.

Explain proliferative capacities of tissues.

Identify stem cells for regeneration.

Identify growth factors for tissue healing and repair.

Explain roles of extracellular matrix in tissue repair.

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Introduction

Introduction

An organism should have the ability to repair/heal the damage caused by toxic insults and inflammation.

The inflammatory response to microbes and injured tissues not only serves to eliminate these dangers but also sets into motion the process of repair/healing.

Even before the inflammatory reaction ends, the body begins the process of healing.

The terms ‘‘healing’’ and ‘‘repair’’ are used interchangeably but repair is one of the process in healing.

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Definition

Definition

Tissue healing is the body response to injury in an attempt to restore normal structure and function.

Replacement of destroyed tissue by living tissue.

Healing involves two (2) distinct processes

Regeneration.

Repair.

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Healing processes

Healing processes

Regeneration occurs when healing takes place by proliferation of parenchymal cells and usually results in complete restoration of the original tissues.

Repair occurs when healing takes place by proliferation of connective tissue elements resulting in fibrosis and scarring.

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Healing processes cont…

Healing processes cont…

Whether healing takes place by regeneration or by repair (scarring) is determined partly by:

Type of cells in the damaged organ.

Destruction or the intactness of the stromal frame work of the organ.

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Healing processes cont…

Healing processes cont…

After many common types of injury, both regeneration and scar formation (repair) contribute in varying degrees to the ultimate healing.

Both processes involve the proliferation of various cells and close interactions between cells and the Extracellular matrix.

The key processes in the proliferation of cells are DNA replication and mitosis as seen in cell cycle.

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Cellular proliferation

Cellular proliferation

Several cell types proliferate during tissue healing.

These include

The remnants of the injured tissue (which attempt to restore normal structure)Regeneration

Vascular endothelial cells (to create new vessels that provide the nutrients needed for the repair process)Repair

Fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration)Repair

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Proliferative capacities of tissues

Proliferative capacities of tissues

Depending upon their capacity to divide, the tissues of the body can be divided into three (3) groups:

Labile tissues.

Stable tissues.

Permanent tissues.

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Labile (continuously dividing) tissues

Labile (continuously dividing) tissues

Cells of these tissues are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells.

These cells continue to multiply throughout life under normal physiologic conditions.

These include

Surface epithelial cells of the epidermis, GIT, respiratory tract, urinary tract, vagina, cervix, uterine endometrium, fallopian tube, ducts of exocrine glands

Haematopoietic cells of bone marrow.

Cells of lymph nodes and spleen.

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Stable tissues

Stable tissues

Cells of these tissues are quiescent and have only minimal replicative activity in their normal state.

However, these cells are capable of proliferating in response to injury or loss of tissue mass.

Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney, and pancreas.

They also include endothelial cells, fibroblasts, and smooth muscle cells, bone, cartilage.

With the exception of liver, stable tissues have a limited capacity to regenerate after injury.

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Permanent tissues

Permanent tissues

Cells of these tissues are terminally differentiated and nonproliferative.

Examples are neurons and cardiac muscle cells.

Injury to brain or heart is irreversible and results in a scar, because neurons and cardiac myocytes cannot regenerate.

Limited stem cell replication and differentiation occur in some areas of the adult brain but also cardiac stem cells may proliferate after myocardial necrosis.

Whatever proliferative capacity may exist in these tissues, it is insufficient to produce tissue regeneration after injury.

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Permanent tissues cont…

Permanent tissues cont…

Skeletal muscle is usually classified as a permanent tissue but satellite cells attached to the endomysial sheath provide some regenerative capacity for this tissue.

In permanent tissues, repair is typically dominated by scar formation.

Most of mature tissues contain variable proportions of three cell types: continuously dividing cells, quiescent cells that can return to the cell cycle, and cells that have lost replicative ability.

Except to tissues composed primarily of nondividing permanent cells (e.g., cardiac muscle, nerve),

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Relationship of parenchymal cells with cell cycle

Relationship of parenchymal cells with cell cycle

Labile cells which are continuously dividing cells remain in the cell cycle from one mitosis to the next.

Stable cells (quiescent cells) are in the resting phase (G0) but can be stimulated to enter the cell cycle.

Permanent cells are non-dividing cells which have left the cell cycle and die after injury.

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Stem cells

Stem cells

In most dividing tissues the mature cells are terminally differentiated and short-lived.

As mature cells die, the tissue is replenished by the differentiation of cells generated from stem cells.

Thus, in these tissues there is a homeostatic equilibrium between the replication, self renewal, and differentiation of stem cells and the death of the mature, fully differentiated cells.

Seen in epithelium of the skin and the GIT, in which stem cells live near the basal layer of the epithelium.

Stem cells differentiate as they migrate to the upper layers of the epithelium for replacement.

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Stem cells cont…

Stem cells cont…

Two (2) important properties of stem cells

Self renewal capacity.

Cells maintain a functional population of precursors for long periods of time.

Asymmetric replication.

When a stem cell divides, one daughter cell undergo differentiation and gives rise to mature cells, while the other remains an undifferentiated to retain its self-renewal capacity.

There are two (2) kinds types of stem cells

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Embryonic stem cells (ES cells)

Embryonic stem cells (ES cells)

Most undifferentiated stem cells.

Present in the inner cell mass of the blastocyst.

Have extensive cell renewal capacity.

Can form specialized cells of all three germ cell layers, including neurons, cardiac muscle, liver cells, and pancreatic islet cells.

Thus normal function of ES cells is to give rise to all cells of the body.

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Adult stem cells

Adult stem cells

Also called tissue stem cells.

Less undifferentiated than ES cells.

Found among differentiated cells within an organ.

Their lineage potential is restricted to those cells.

They also have self-renewal capacity, though limited.

They are involved in tissue homeostasis.

They maintain the compartment size in tissues with

high turnover .e.g. skin, bone marrow, and GIT epithelium.

low cell turnover, such as heart and blood vessels.

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Molecular control of healing process

Molecular control of healing process

The proliferation of cells involved in tissue healing is driven by low molecular weight proteins called growth factors.

These growth factors have the capacity to stimulate cell division and proliferation.

Some of the factors, known to play a role in the healing process itself.

The production of polypeptide growth factors and the ability of cells to divide in response to these factors are important determinants of the adequacy of the repair process.

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Growth factors

Growth factors

These are proteins that are involved in cell proliferation, cell migration, cell differentiation, stimulation of angiogenesis, and fibrogenesis.

They induce cell proliferation by binding to specific receptors and affecting the expression of genes.

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Sources of Growth factors

Sources of Growth factors

Platelets, activated after endothelial damage.

Damaged epithelial cells.

Circulating serum growth factors.

Macrophages.

Lymphocytes recruited to the area of injury.

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List of Growth factors

List of Growth factors

Epidermal growth factor (EGF).

Transforming growth factor-α (TGF-α).

Hepatocyte growth factor (HGF) (scatter factor).

Vascular endothelial growth factor (VEGF).

Platelet-derived growth factor (PDGF).

Fibroblast growth factors (FGFs), including acidic (FGF-1) and basic (FGF-2).

Transforming growth factor-β (TGF-β).

Keratinocyte growth factor (KGF) (i.e., FGF-7).

Refer Handout 12.1 for additional information.

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General functions of Growth factors

General functions of Growth factors

They promote entry of cells into the cell cycle.

They relieve blocks on cell cycle progression (thus promoting replication)

They prevent apoptosis.

They enhance the synthesis of cellular proteins in preparation for mitosis.

A major activity of growth factors is to stimulate the function of growth control genes (proto-oncogenes)

Because mutations of proto-oncogenes gives oncogenes hence oncogenesis.

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Signaling mechanisms of growth factor receptors

Signaling mechanisms of growth factor receptors

Most growth factors function by binding to specific cell surface receptors and triggering biochemical signals in cells.

In general, these signals lead to the stimulation or repression of gene expression.

Signaling may occur directly in the same cell that produces the factor (autocrine signaling), between adjacent cells (paracrine signaling), or over greater distances (endocrine signaling).

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Signaling mechanisms of growth factor receptors

Signaling mechanisms of growth factor receptors

Receptor proteins are generally located on the cell surface, but they may be intracellular.

for intracellular the ligands must be sufficiently hydrophobic to enter the cell (e.g., vitamin D, or steroid and thyroid hormones).

On the basis of their major signaling transduction pathways, plasma membrane receptors fall into three (3) main types.

Receptors with intrinsic kinase activity.

G protein–coupled receptors.

Receptors without intrinsic enzymatic activity.

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Extracellular Matrix in tissue repair

Extracellular Matrix in tissue repair

Tissue repair depends not only on growth factor activity but also on interactions between cells and Extracellular Matrix (ECM) components.

Extracellular Matrix is a complex of several proteins that assembles into a network that surrounds cells and constitutes a significant proportion of any tissue.

An intact ECM is required for tissue regeneration, and if the ECM is damaged, healing can be accomplished only by scar formation (repair)

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Role of Extracellular Matrix in tissue repair

Role of Extracellular Matrix in tissue repair

ECM sequesters water, providing turgor to soft tissues, and minerals, giving rigidity to bone.

It also regulates the proliferation, movement, and differentiation of the cells living within it, by supplying a substrate for cell adhesion and migration and serving as a reservoir for growth factors.

The ECM is constantly being remodeled.

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Basics forms of Extracellular matrix

Basics forms of Extracellular matrix

Interstitial matrix

Found in the spaces between cells in connective tissue, and between epithelium and supportive vascular and smooth muscle structures.

It is synthesized by mesenchymal cells (e.g., fibroblasts) and tends to form a three-dimensional, amorphous gel.

Its major constituents are collagens (fibrillar and nonfibrillar), fibronectin, elastin, proteoglycans, hyaluronate.

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Basics forms of Extracellular matrix

Basics forms of Extracellular matrix

Basement membrane

The basement membrane lies beneath the epithelium.

It is synthesized by overlying epithelium and underlying mesenchymal cells.

It tends to form a platelike “chicken wire” mesh.

Its major constituents are amorphous nonfibrillar type IV collagen and laminin.

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Components of the Extracellular Matrix (ECM)

Components of the Extracellular Matrix (ECM)

There are three (3) basic components of ECM

Fibrous structural proteins such as collagens and elastins, which confer tensile strength and recoil.

Water-hydrated gels such as proteoglycans and hyaluronan, which permit resilience lubrication.

Adhesive glycoproteins that connect the matrix elements to one another and to cells.

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Components of the Extracellular Matrix (ECM) cont…

Components of the Extracellular Matrix (ECM) cont…

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Roles of the Extracellular Matrix (ECM)

Roles of the Extracellular Matrix (ECM)

Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity

Control of cell growth

Maintenance of cell differentiation.

Scaffolding for tissue renewal.

Establishment of tissue microenvironments.

Storage and presentation of regulatory molecules.

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Growth factors involved in ECM deposition

Growth factors involved in ECM deposition

Transforming Growth Factor β (TGF-β).

Platelet Derived Growth Factor (PDGF).

Fibroblast Growth Factor (FGF).

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Key points

Key points

Healing process starts almost as soon as the inflammatory process begins.

Healing involves regeneration and repair.

Tissues are divided into labile, stable, and permanent, according to the proliferative capacity of their cells.

Growth factors stimulate cell proliferation , differentiation, and other cellular responses.

The ECM consists of the interstitial matrix between cells and basement membranes underlying epithelia.

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Review questions

Review questions

Define tissue healing.

List two (2) factors which determine whether the wound will heal by either regeneration or repair.

List three (3) roles of growth factors in tissue healing.

What are the components of Extracellular matrix?

Explain five (5) roles of Extracellular matrix in tissue healing.

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References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 48.

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 58-64.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg.165, 170.

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