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Lecture 6

Healing and Repair


Dr. Nabila Hamdi
MD, PhD
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ILOs
• Know the classification of human cells according to their ability for
proliferation.
• Understand the mechanism of cellular regeneration.
• Identify the types of repair.
• Describe the different steps of tissue repair, including the cell types and
growth factors involved, and the approximate timetable for the tissue
repair process.
• Compare healing by first intention (primary union) and second intention
(secondary union) in terms of time, sequence of events, morphologic
changes, and final outcome..
• Be oriented with the factors affecting the process of repair.

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Outline
1. Overview
2. Cell Regeneration
• Control of cell growth, cell cycle
• Growth factors
• Extracellular matrix
3. Repair by Connective Tissue
• Angiogenesis
• Fibrosis (Scar formation)
• Scar Remodeling
4. Wound Healing
• Healing by first intention
• Healing by second intention
• Wound strength
5. Factors Affecting Healing
6. Overview of the Inflammatory-Reparative Response

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Overview

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Overview

Regeneration or Fibrosis??
(Scar)

Cells ECM

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The Cell Cycle
(S) DNA synthesis phase (G2) Premitotic growth phase

(M) Mitotic phase


(G1) Presynthetic growth
phase

Cell cycle is the sequence of events that control DNA replication and mitosis
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Cell Cycle Regulation

Progression through the cell cycle from G1 is regulated by proteins called cyclins.
Cyclin form complexes with enzymes called cyclin-dependent kinases (CDKs)
which become activated.
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Proliferative Capacities of Tissues
Labile tissues Stable tissues Permanent tissues
(Continuously dividing) - Quiescent in the G0 stage. - Terminally differentiated
- Cells are continuously being - Minimal replicative activity and nonproliferative in
lost and replaced. in their normal state. postnatal life
- Can readily regenerate after - Capable of proliferating in - Repair is typically
injury. response to injury or loss of dominated by scar
tissue mass. formation

Examples:
Examples: Examples:
 Hematopoietic cells in BM
 Liver  Cardiac muscle
 Stratified squamous
surfaces (skin, oral cavity,  Kidney  Skeletal muscle
vagina, and cervix)  Pancreas  Neurons
 Columnar epithelium of  Endothelial cells,
GIT, uterus fibroblasts, and smooth
muscle cells
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How Does Regeneration Occur?
Growth factor (GF)

ECM

Growth factor receptor (GFR)


Cell

Cell Response
(proliferation, locomotion, and differentiation)

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Soluble Mediators
Definition:
by convention "growth factor" is used for a protein that expands cell populations by
stimulating cell division and by promoting cell survival.

General Properties:
 Most growth factors have pleiotropic effects: in addition to stimulating cellular
proliferation, they stimulate migration, differentiation and contractility, and
enhance the synthesis of specialized proteins (such as collagen in fibroblasts)

 A growth factor may act on a specific cell type or on multiple cell types

 They induce cell proliferation by binding to specific receptors and affecting the
expression of growth control genes

 Adjacent cells communicate via gap junctions (narrow, hydrophilic channels that
effectively connect the two cell cytoplasm), allowing movement of small ions,
various metabolites, second messengers but not larger macromolecules.

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Soluble Mediators
Extracellular Signaling Mechanisms

 Autocrine Signaling: substance acts on the


cell that secretes it.
Example: compensatory hyperplasia (e.g., liver
regeneration)

 Paracrine signaling: a substance affects


cells in the immediate vicinity of the cell that
released the agent.
Example: inflammatory cells recruitment to the
site of infection and wound healing.

 Endocrine signaling: a regulatory substance


is released into the bloodstream and acts on
target cells at a distance.
Example: hormones
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Soluble Mediators
 Cell Surface Receptors
 Receptors with intrinsic kinase activity can activate other intracellular proteins (e.g.,
RAS, phosphatidylinositol 3-[PI3] kinase, phospholipase Cγ [PLC-γ]).

 G-protein-coupled receptors: largest family of plasma membrane receptors. Activate


cyclic AMP (cAMP), and generates inositol-1,4,5,-triphosphate (IP3), which releases
calcium from the endoplasmic reticulum.

 Receptors without intrinsic enzymatic activity: Phosphorylation of Janus kinases (JAKs)


activates cytoplasmic transcription factors called STATs (signal transducers and
activators of transcription), which shuttle directly into the nucleus.

 Intracellular Receptors
ligands must be sufficiently hydrophobic to enter the cell (e.g., vitamin D, or steroid and
thyroid hormones). Ligand binding leads to the formation of receptor-ligand complexes that
directly associate with nuclear DNA and activate or turn off gene transcription.

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Cell Surface Receptors
epinephrine, vasopressin ,
serotonin, histamine, and
EGF, VEGF, FGF, HGF glucgon

Transcription factors bind to gene


promoters and enhancers to
trigger or inhibit transcription

Not all ligands induce


stimulatory signals!
RAS activation stimulates the mitogen-activated protein (MAP) kinase cascade,
which is involved in the intracellular signaling of many
growth factors (EGF, VEGF, FGF, HGF…)
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Extra-Cellular Matrix (ECM)

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Extra-Cellular Matrix (ECM)
Components:
 The interstitial matrix between cells
 The basement membranes (nonfibrillar collagen and laminin)
 Integrins are transmembrane glycoproteins, the main cellular receptors for
ECM components
 Collagen is a structural proteins that confer tensile strength
 Elastin confers tissue elasticity (ability of tissues to recoil and return to a
baseline structure after physical stress)
 Adhesive glycoproteins connect cells to underlying ECM components. They
include fibronectin (major component of the interstitial ECM) and laminin
(major constituent of basement membrane)
 Proteoglycans form highly hydrated compressible gels conferring lubrication
(such as in the cartilage in joints) and serve as reservoirs for growth factors
secreted into the ECM
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Extra-Cellular Matrix (ECM)
Functions:
 Mechanical support to tissues (collagens and elastin)

 Substrate for cell growth and the formation of tissue microenvironments.

 Regulates cell proliferation and differentiation

 Determination of cell orientation (polarity)

 An intact ECM is required for tissue regeneration, and if the ECM is


damaged, repair can only be accomplished by scar formation.

 Storage and presentation of regulatory molecules (FGF is excreted and


stored in the BM in normal tissues, to be readily involved after local injury)
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Repair by Connective
Tissue

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Repair by Connective Tissue
When?
 If nondividing cells are injured.
 If tissue injury is severe or chronic, and results in damage to parenchymal cells and
epithelia as well as the stromal framework
How?
1. within 24 hours of injury: fibroblasts emigration, and fibroblast and endothelial
cell proliferation.

2. By 3 to 5 days, granulation tissue appears. This specialized tissue is characteristic


of healing; it is pink, soft with a granular gross appearance, such as that seen
beneath the scab of a skin wound. Its histologic appearance is characterized by
proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis),
in a loose ECM.

3. Progressively, granulation tissue accumulates connective tissue matrix, eventually


resulting in the formation of a scar, which may remodel over time.
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Repair by Connective Tissue
1. Angiogenesis (Neovascularization)

VEGF
FGF

Capillary sprouting
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Repair by Connective Tissue
Angiogenesis is a critical process in:
 Healing at sites of injury
 Development of collateral circulations at sites of
ischemia
 Allowing tumors to increase in size beyond the
constraints of their original blood supply

 Targeting angiogenesis:
• Stimulation, e.g., to improve blood flow to a heart
ravaged by coronary atherosclerosis.
• Inhibition, to frustrate tumor growth.
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Repair by Connective Tissue
2. Migration and Proliferation of Fibroblasts
 Driven by PDGF, FGF, and TGF-β secreted by activated endothelium
and chronic inflammatory cells.

3. ECM Deposition (Scar Formation)


 Fibroblasts progressively assume a more synthetic phenotype, and
hence there is increased deposition of ECM.
 Collagen synthesis, in particular, is critical to the development of
strength in a healing wound site.

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Keloid
Excess collagen deposition in the skin forming
a raised scar
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Repair by Connective Tissue
The outcome of the repair process is, in part, a balance between
ECM synthesis and degradation

4. Remodeling of Connective Tissue


 The degradation of collagens and other ECM components is
accomplished by a family of matrix metalloproteinases (MMPs),
which are dependent on zinc ions for their activity
 Interstitial collagenases, which cleave fibrillar collagen (type 1,2
and 3)
 Gelatinases (Type IV collagenases), which degrade amorphous
collagen and fibronectin
 MMPs are produced by a variety of cell types (fibroblasts,
macrophages, neutrophils, some epithelial cells)
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Wound Healing
Clean, uninfected surgical incision approximated by surgical sutures

The incision causes only focal disruption of epithelial basement membrane


continuity and death of a relatively few epithelial and connective tissue cell

Epithelial regeneration predominates over fibrosis


(a small scar is formed)

Healing by first intention or primary union

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Wound Healing
Large wounds, abscess formation, ulceration, infarction

Cell or tissue loss is more extensive


Regeneration of parenchymal cells alone
cannot restore the original architecture

Abundant development of granulation tissue


Accumulation of ECM and scarring

Healing by second intention or secondary union Wound Care in the Wilderness, January 24, 2013

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Wound Healing by First Intention
Neutrophils are seen at the incision margin, migrating
toward the fibrin clot.
Basal cells of the epidermis begin to show increased mitotic
activity.

Neutrophils have been largely replaced by macrophages


Granulation tissue progressively invades the incision space
Epithelial cell proliferation continues
By day 5, neovascularization reaches its peak as granulation
tissue fills the incisional space
 Collagen fibers are present at the incision margins

 Continued collagen accumulation and fibroblast


proliferation
 leukocyte infiltrate, edema, and increased 2nd week
vascularity are substantially diminished.

By the end of the first month, the scar comprises a cellular
connective tissue largely devoid of inflammatory cells and
covered by an essentially normal epidermis.
The tensile strength of the wound increases with time to
reach 70%-80% by 3 months 26
Wound Healing by Second Intention

A larger clot or scab forms at the surface of the wound


Inflammation is more intense (larger necrotic debris,
exudate, fibrin)

Much larger amounts of granulation tissue are formed

Greater mass of scar tissue.


Secondary healing involves wound contraction.
Large skin defects may be reduced to 5% to 10% of their original size
within 6 weeks, largely by contraction
Myofibroblasts: fibroblasts exhibiting many of the ultrastructural
and functional features of contractile smooth muscle cells. 27
Wound Strength
• Carefully sutured wounds have approximately 70% of the strength
of unwounded skin, largely because of the placement of the
sutures.

• When sutures are removed, usually at 1 week, wound strength is


approximately 10% of that of unwounded skin, but this increases
rapidly over the next 4 weeks.

• The recovery of tensile strength results from collagen synthesis


exceeding degradation during the first 2 months

• Wound strength reaches approximately 70% to 80% of normal by


3 months but usually does not substantially improve beyond that
point.

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Factors Affecting Healing
 Infection is the single most important cause of delay in healing; it prolongs
the inflammation phase of the process and potentially increases the local
tissue injury.

 Nutrition has profound effects on wound healing. Protein deficiency and


particularly vitamin C deficiency, inhibits collagen synthesis and retards healing.

 Glucocorticoids have well-documented anti-inflammatory effects, and their


administration may result in poor wound strength due to diminished fibrosis.

 Poor perfusion, due to arteriosclerosis, diabetes…

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Pathways of Reparative Responses

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• Complete restoration can occur only in tissues composed of stable and
labile cells.

• Even if cells are able to divide, extensive injury will probably result in
incomplete tissue regeneration and at least partial loss of function.

• Injury to tissues composed of permanent cells must inevitably result


in scarring with, at most, attempts at functional compensation by the
remaining viable elements (myocardial infarct).

• Depending on the type and extent of injury, the nature of the injured
tissue, and persistence of inflammatory stimuli, injury results often in
some degree of residual scarring.

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References

• ROBBINS Basic Pathology 8th Edition

• Basic Pathology 7th Edition, by Kumar, Cotran and Robbins

• Fibroblast cover image:


http://www.gegeonline.nl/anatomie/bindweefsel.html

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