Pathology PHT 218
Unit 3
Repair and Regeneration
Repair and Regeneration
Tissue Repair
may start early after tissue damage
• 1. Regeneration
– Restoration of original tissue architecture and
function
– by parenchymal cells of the same type
• 2. Repair
– Replacement by connective tissue (scarring)
– There will be alterations in both architecture and
function
Regeneration: Cell requirements
CELLULAR PROLIFERATION
Tissues of the body are divided into three groups:
• Continuously dividing (labile) tissues
• Stable tissues
• Permanent tissues
Tissue types
1. permanent
• nonproliferative in postnatal life
• neurons , cardiomyocytes
2. stable
• regeneration as response to injury
• parenchyma – liver, pancreas, renal tubule
3. labile
• continuous regeneration from stem cells (self-renewal)
• hematopoietic cells in bone marrow
• surface epithelia – skin, oral cavity, vagina, cervix
• duct epithelia – salivary glands, pancreas, biliary tract
• mucosas – GIT, uterus, fallopian tubes, urinary bladder
CELLULAR PROLIFERATION
Tissues of the body are divided into three groups:
• Continuously dividing (labile) tissues
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•
•
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cells are continuously proliferating
can easily regenerate after injury
contain a pool of stem cells
examples: bone marrow, skin, GI epithelium
CELLULAR PROLIFERATION
• Stable tissues
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•
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cells have limited ability to proliferate
limited ability to regenerate (except liver!)
normally in body, but can proliferate if injured
examples: liver, kidney, pancreas
CELLULAR PROLIFERATION
• Permanent tissues
• cells can’t proliferate
• can’t regenerate (so injury always leads to scar)
• examples: neurons, cardiac muscle
The Cell Cycle and Different Cell Populations
The parenchyma are the functional parts of an organ in the body.
This is in contrast to the stroma, which refers to the structural
tissue of organs, namely, the connective tissues.
Organ
brain
heart
kidney
liver
Parenchyma
neurons and glial cells
myocyte
nephron
hepatocyte
lungs
pancreas
spleen
Lung parenchyma
Islets of Langerhans and Pancreatic acini
white pulp and red pulp
Regeneration
• Regeneration results in the replacement of lost cells
by their own kind, thereby returning the tissue to
normal structure and function
• Labile or stable cells
• Intact stroma (connective tissue) and basement
membranes
• Parenchymal cells (functional cells) migrate across
existing stromal framework and multiply to restore
tissue integrity .
Regeneration: Hindrances
• Destruction of stroma
– disturbed proliferation of parenchymal cells
– Replacement of stroma
• Excessive exudation/infection
• Polymorphonucleocytes(PMNs) secrete numerous
proteases (collagenases, elastases) which digest the
basement membrane and supporting connective
tissues
• Bacteria often have similar enzymes and/or toxins
which may kill the parenchymal or inflammatory
cells
• Excessively large defects
• Permanent cells
Repair
• When the requirements for regeneration are
not met, then the gaps produced by lost cells
heal by connective tissue replacement
• Repair by fibrous tissue/connective tissue/
granulation tissue
• Wound healing
Cell-ECM interactions
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not only cells!
EMC plays important role in healing
interstitial matrix – by fibroblasts
basement membrane – by fibroblast and epithelium
components
– Collagen, elastin, fibrillin, glycoproteins and proteoglycans
and hyalouronans.
Cell-ECM interactions
• ECM function
– mechanical support
– determination of cell polarity
– control of cell growth
– maintenance of cell proliferation
– establishment of tissue microenvironments
– storage of regulatory molecules
Replacement of necrotic tissue
• resorption by macrophages
• dissolution by enzymes
• replacement by granulation tissue
– uniform mechanism irrespective of inicial trigger
– the same microscopic appearance
– The steps are:
1. angiogenesis
2. migration and proliferation of fibroblasts
3. deposition of ECM
4. maturation and reorganization
Repair by Connective Tissue
• Conditions for regeneration are not met
• Four components to this process:
1. Formation of new blood vessels (angiogenesis)
2. Migration and proliferation of fibroblasts
(fibroblast is a type of cell that synthesizes the
extracellular matrix and collagen, the structural
framework )
3. Deposition of Extracellular matrix, synthesis of
collagen (scar formation)
4. Maturation, contraction, and organization of
fibrous tissue (remodeling of scar)
Granulation tissue
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•
•
•
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new-formed connective tissue, apparent from 3rd day
thin-walled capillary vessels
fibroblasts
loose extracellular matrix
stimulation
– PDGF, VEGF, FGF, TGF, TNF, EGF
• inhibition
– INFalfa, prostaglandins, angiostatins
• control
– cyclins, cyclin dependent kinases
Granulation tissue
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•
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pink soft granular appearance
richly vascularized
highly cellular
myxoid matrix
inflammatory cells
• e.g. surface of wounds, bottom of ulcers
1. Angiogenesis
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neovascularization
x vasculogenesis (embryonic process only)
highly complex phenomenon
angiogenic factors (FGF, VEGF)
antiangiogenic factors
healing, collateral circulation, tumors
1. Angiogenesis
2. Role of (Fibrosis) Fibroplasia
• Fibroblasts proliferate replace fibronectin-fibrin with
collagen contribute ECM
• Fibroplasia – fibrous repair
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–
–
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Formulation of Granulation tissue
Infiltration of fibroblasts
Collagen laid down in random pattern
Scar tissues excessive if inflammation re-initiated
3. Role of extracellular matrix in wound healing and scar formation
• Extracellular matrix (ECM) is formed by specific secreted macromolecules
that form a network on which cells grow and migrate along
• ECM proteins assemble into two general organizations
– Interstitial matrix (present between cells)
– Basement membrane [BM] (produced by epithelial and mesenchymal
cells and is closely associated with the cell surface)
Three groups of macromolecules constitute the ECM
1. Fibrous structural proteins
– Collagen(18 types) – I, III, IV, V; tensile strength
– elastin (+ fibrillin) – return to normal structure after stress
2. Adhesive glycoproteins
– adhesion, binding ECM to cells (fibronectin, laminin)
3. Proteoglycans and Hyaluronic
Acid(hyalouronans) - lubrication (gels)
4. Maturation & Remodeling
– Initial scar formation takes weeks
– Scar matures
• Longest part of inflammation (over 1 yr)
• Re-absorb temporary vasculature
– Scar shrinks (contraction) & changes color
– Scar remodels
• Collagen fibers re-align with stress (SAID)
• Less tensile strength than tissue it replaces
The phases of cutaneous wound healing
Injury leads to accumulation of platelets and
coagulation factors.
Coagulation results in fibrin formation and release
of PDGF and TGF-b and other inflammatory
mediators by activated platelets. This leads to more
Neutrophil recruitment which signals the
beginning of inflammation (24 h).
After 48 h macrophages replace neutrophils.
Neutrophils and macrophages are responsible for
removal of cellular debris and release growth
factors to reorganize the cellular matrix.
At 72 hours the proliferation phase begins as
recruited fibroblasts stimulated by FGF and TFGb begin to synthesize collagen. Previously formed
fibrin forms initial matrix for fibroblasts
Collagen cross-linking and reorganization occurs
following months after injury in the remodeling
phase of repair.
Wound contraction follows in large surface
wounds and is facilitated by actin-containing
fibroblasts (myofibroblasts)
Skin Wound healing
Skin wounds are classically described to heal by either primary or secondary
intention and the distinction is made by the nature and extent of the wound
First intention healing
Second intention healing
wounds with clean opposing edges (surgical
incision, should form a narrow scar due to small
amount of granulation tissue required to fill the
gap)
wounds with separated edges (trauma that
requires abundance of granulation tissue for
wound closure)
Pathological aspects of healing
• proud flesh (caro luxurians)
– excessive amount of Granulation tissue(GT)
• keloid
– excessive amount of collagen
• hyaline plaques
– serous membranes (spleen, pleura)
Complications of wound healing
• Deficient scar formation
– Wound dehiscence (premature "bursting" open of a
wound along surgical suture)
– Ulceration
• Excessive formation of scar tissue
– Keloid (excessive collagen deposition)
– Desmoid (aggressive fibromatosis, semi-malignant)
• Contracture
Wound dehiscence
Keloid
Wound ulceration
Contracture
Keloids: Beyond the Borders
• Excess Deposition
of Collagen Causes
Scar Growth
Beyond the Border
of the Original
wound
Tx: XRT, steroids, silicone sheeting, pressure, excise.
often Refractory to Tx & not preventable
Factors that influence wound healing
I. Systemic factors
• Malnutrition
– Protein deficiency
– Vitamin C deficiency (inhibition of collagen synthesis)
• Metabolic status
– e.g Diabetes mellitus
• Consequence of microangiopathy
– Cortison treatment
• inhibits inflammation and collagen synthesis
• Circulatory status
– Inadequate blood supply due to ateriosclerosis
– Varicose veins (retarded venous drainage)
Factors that influence wound healing
II. Local Factors
• Infection (single most important reason for delayed wound healing)
• Foreign bodies
– suture material, bone and wood splinters ….
• Mechanical factors
– Early movement
– Pressure