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Mo'ath Al-Rjoob

Shayma'a Dibian

Hadeel Alfawaz 1
 Tissue repair

 The last paper of this sheet includes two slides from the previous lecture
(chronic inflammation); Dr. Mo'ath gave them to group 1 with this lecture
(tissue repair). Please read them before starting with a new subject.
 You can ignore the extra notes, the Dr. didn't mention them ☺

In fact, the inflammatory response to microbes and injured tissues is not

just to eliminate these dangers, but also to induce the process of repair.
The topics included in this lecture are:

1. The general mechanism of tissue repair.

2. The principal growth factors involved in repair.

The Repair of damaged tissue occurs by two types of reactions:

1. Regeneration:

Replacement of damaged tissue by similar parenchymal cells as a result

of uninjured cells proliferation (i.e.: from the intact framework), or stem
cell differentiation.

This process takes place just in the case of a mild damage to a tissue that
is capable to proliferate.

Examples:

• Liver regeneration after partial hepatectomy.

• Superficial skin wounds.
• Resorption of exudate in lobar pneumonia.
 Extra note: lobar pneumonia is an infectious disease culminates in intra-
alveolar edema that will be resorbed by macrophages in the case of
complete recovery.

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2. Fibrosis:

The formation of a connective tissue scar in the case of severe damage

to the supporting cells (i.e. loss of the whole framework) or to cells that
lack the ability to proliferate.

This process could happen in the case of:

❖ Acute injury: starts within minutes, and lasts for days to be fully
generated.
Examples:

• Deep excisional wounds.

• Myocardium infarction.

 Extra note: If fibrosis develops in a tissue with an inflammatory exudate

(especially in acute inflammation), it's called organization, such as the
formation of a scar in lobar pneumonia disease (mentioned in the picture
below).

❖ Chronic injury: prolonged formation of scar; lasts for years.

Examples:

• Cirrhosis.
• Chronic pancreatitis.
• Pulmonary fibrosis.

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 ❖ Remember:
✓ The factors which determine the type of response in repairing
process are: the extent of injury along with the type of the
damaged tissue.

❖ Healing (repair) is a combination of regenerative and fibrotic

processes.

Note: regeneration and fibrosis could happen in the same time during the
process of repair, or could happen individually.

Types of cells according to their proliferative capacity:

• Labial cells :
Cells which are continuously being lost and must be continuously
replaced by new cells that are derived from tissue stem cells.

Examples:

✓ Hematopoietic cells in bone marrow.

✓ Many surface epithelia such as skin epidermis and GI lining.
Note: GI epithelial cells are replaced continuously every 5 days.

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 • Stable cells(quiescent):
Cells which are normally in G0 phase of the cell cycle and hence not
proliferating, but they are capable of dividing under the stimulation of
certain factors in the case of injury or loss of tissue mass.

Examples:

✓ Liver during hepatectomy.

✓ Some types of kidney cells.
✓ Smooth muscles.
✓ Skeletal muscles (In very rare circumstances; in the case of
injury or increasing the workload "hyperplasia").

• Permanent (non dividing cells):

Cells which are always in G0 phase, which can't regenerate at all.

Examples:

✓ Cardiac muscles.
✓ The majority of neurons.
Note: the scar that will be formed to replace the damaged neuron (e.g.:
in the case of stroke) called gliosis which involves the proliferation of
glial cells in CNS.

The picture below represents the regulation of cell population (labial

cells), showing the capability of baseline cells (formed from stem cells)
to proliferate upon the stimulation by specific growth factors. Or to
differentiate giving mature cells lacking the ability to proliferate.
Apoptosis also could drive these cells to death.

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 The cell-cycle landmarks:

The cell cycle contains two major phases:

• Interphase: including G1, S & G2 subphases.

• Mitosis.

The picture below shows the 3 types of cells which are already discussed
before:

❖ The continuous division of labial cells.

❖ Stable cells normally in G0, but upon the stimulation they will enter
the cycle.
❖ Permanent cells that can't enter the cycle at all; always in the G0
phase.
There are also 3 check points to ensure that the replication of DNA is in
the right way; avoiding any error that could result in malignant
transformation.

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 Stem cells:
Undifferentiated biological cells that can differentiate into
specialized cells and can divide (through mitosis) to produce more stem
cells.

✓ Characteristics of stem cells:

• Self-renewal capacity.
• Asymmetric replication:
A stem cell divides into one mother cell that is identical to the original
stem cell, and another daughter cell that is differentiated. (Hence, the
number of stem cells will be constant in each division).

• The capacity to develop into multiple lineages.

• Extensive proliferative potential (limitless proliferation).
• High rate of proliferation without errors.

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✓ Types of stem cells:

• Embryonic stem cells :

Pluripotent cells that can give rise to all tissue types, including:
mesoderm, ectoderm and endoderm.

• Adult stem cells:

Having a restricted differentiation capacity.

• Induced pluripotent stem cells (iPSCs): "under research".

Adult stem cells reprogrammed to embryonic cells by the addition of
specific genes, giving any type of tissue. Genes (that will change
the cell into a
pluripotent one).

Embryonic stem
cells after
differentiation

The major advantage of this technique is to replace the damaged cells

which lack the ability to proliferate with new cells from the same type.
Ex: in the case of damaged cardiac muscles or damaged neurons.

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 The use of embryonic stem cells in medical field:

• Study of specific cell signaling and differentiation steps.

• Production of knockout mice.

>>The Dr. didn't say anything about this point

This video may help u to get the idea: https://youtu.be/PooN1OvgDKE

• Potentially, generation of specific cell types to regenerate

damaged tissue (regenerative medicine).

Examples of adult stem cells location:

Bone marrow Hematopoietic cells

Liver In hering canal
Skeletal muscle Satellite cells (quiescent )
Intestine Base of crypts

Skin Hair follicle bulge

Eyes Corneal stem cells

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 Polypeptide growth factors:
Chemical mediators that affect the cell growth by binding to specific
receptors on the cell surface or intracellularly.

✓ They are the most important chemical mediators affecting cell

growth; by controlling the expression of proto-oncogenes.

Proto-oncogenes: normal genes involved in cell growth and proliferation or

inhibition of apoptosis.

>we will know more about them in neoplasia lecture.

✓ Present in serum or produced locally (depending on the type of

growth factor).
✓ Exert pleiotropic effect (multiple functions) including:
Proliferation, cell migration, differentiation and tissue remolding. Also
one function can be produced by many different growth
factors(collaboration between GFs).

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 Examples of growth factors:
• EGF (epidermal GF) & TGF-α (transforming GF): "the receptor is
ErbB-1".
Functions:

✓ Mitogenic (stimulate mitosis) for epithelial cells and fibroblasts.

✓ Migration of epithelial cells.
Ex: after the differentiation of hair follicle stem cells, they will migrate
toward the epidermis where they will settle.

• PDGF (platelet derived GF):

✓ Migration and proliferation of fibroblasts, smooth muscle cells
and monocytes.
✓ Chemoattractant during the inflammatory process.

• FGF (fibroblast GF):

✓ Mitogenic for fibroblasts and epithelial cells.
✓ Angiogenesis: The process of new blood vessels development
from existing vessels.
✓ Acts as a Chemotactic for fibroblasts; inducing by that the
wound healing process.

• VEGF (vascular epithelial GF):

✓ Increases the vascular permeability during angiogenesis
process.

• HGF/ Scatter factor (hepatocyte GF):

✓ Mitogenic to most epithelial cells specially hepatocytes.
✓ Promotes the migration (scattering) of cells.

• TGF-β (transforming GF):

✓ Very strong anti-inflammatory mediator; by inhibiting most of
epithelial cells and leukocytes, and increasing expression of cell
cycle inhibitors >> (Cip/Kip , INK4/ARF).
✓ Potent fibrogenic agent; by stimulating fibrosis >>

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 (↑ Fibroblasts chemotaxis, production of ECM, ↓ proteases,
↑proteases inhibitors).

Mechanism of action for TGF-β:

1. TGF-β binds to 2 types of serine/threonine kinase receptors (type I
&II).

2. The receptors will phosphorylate cytoplasmic transcription factors

called "Smads".

3. Smads then enter the nucleus and associate with other DNA binding
proteins activating or inhibiting gene transcription.
This video may help u in memorizing the mechanism:

https://youtu.be/G3CSpUpMBDg

How do growth factors exert their function?

Depending on the type of secretory cell, the type of the growth factor
and its concentration, classified into:

• Autocrine signal: binds to receptors located at the same secretory

cell.
• Paracrine signal: binds to receptors located at adjacent cells.
• Or Endocrine signal: secreted in the bloodstream, binds to distant
target cells (similar to hormones).

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 Types of growth factor receptors:

• Receptors with intrinsic tyrosine kinase activity, which include 3

pathways:
✓ PI3 kinase pathway.

✓ MAP-kinase pathway:
Ex: binding of EGF (epidermal growth factor) & HGF (Hepatocyte growth
factor), which culminates in transcription factor activation and DNA
replication.

✓ IP3 pathway.

• Transmembrane G -protein coupled receptors :

✓ By c-AMP & Ca2+ pathway.
Note: chemokines bind to this type of receptors.

• Receptors lacking intrinsic tyrosine kinase activity that recruit

kinases:
✓ By JAK/STAT pathway.
Ex: binding of cytokines (some types of cytokines lead to growth
stimulation).

• Steroid receptors: located intracellularly.

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The Dr. said that the most important thing to know above is the final step; which will
affect the cell growth by either stimulating or inhibiting the gene expression.

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The last two slides of chronic inflammation:
The inflammatory process is actually a protective response that is
essential for survival, but if there is a defect in one or more of the
inflammatory cascades; harmful reactions will be produced.

As you know, our immune system is subdivided into two main types:

• Innate immunity: nonspecific defense mechanisms.

• Acquired immunity: a specific type of response.

And because of the crucial contribution of inflammation to stimulate the

innate immunity as a response to any type of invaders, we consider
inflammation as a nonspecific response.

So any defect of this important response, our body will be more

susceptible to infections.

Briefly, the consequences of defective inflammation are:

❖ Susceptibility to infections because of defective innate immunity.

❖ Delayed repair because of :
• Delayed clearance of debris and necrotic tissue.
• Lack of stimuli for the process of repair.

However, having an excessive inflammatory response against any

offending agent could result in:

❖ Allergic reactions (hypersensitivity): the body's way of responding

to a harmless agent (e.g.: dust, pollen).

❖ Autoimmune disorders: when your immune system starts to

attack healthy cells in your body.

❖ Atherosclerosis: a plaque of fat and other substances formed

inside the arteries.
Extra Note: excessive inflammatory and fibroproliferative responses lead to
thickening of the arterial wall and the formation of that plaque.
❖ Ischemic heart disease.
Wish you all the best ☺

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