First Foundations in Pathology

Part 3: Growth and Repair

Paul G. Koles, MD
Asst. Prof. Pathology and Surgery
Director of Pathology Education
Boonshoft School of Medicine at Wright State University

Overview Part 3

Control of normal cell growth and regeneration

Extracellular matrix & cell-matrix interactions
Repair by connective tissue (fibrosis)
Wound healing

Repair following inflammation:

two simultaneous processes

: replacement of
injured/necrotic cells by cells of same
type, often leaving no evidence of
previous injury

: replacement
of injured/necrotic cells by connective
tissue, leaving a permanent scar
(microscopic or macroscopic)

Control of cellular population

Cell Cycle
PHASES of
Cell Cycle:
G1:
S:
G2:
M:
G0:

Correlation of Cell Cycle and Tissue Types

Continuously dividing (labile) cells:
Surface epithelium and excretory ducts of glands (skin,
gi / gu mucosa, biliary tract, pancreas)
Marrow hematopoietic cells
Stem cells in multiple organs (immature, undifferentiated
cells)

Quiescent (stable) cells in G0:

Organ parenchymal cells (liver, kidneys)
Mesenchymal cells (fibroblasts, smooth muscle,
endothelium, chondrocytes, osteocytes)

Nondividing permanent cells (cant re-enter cell

cycle)
Neurons, skeletal & cardiac myocytes

Control of Passage through Cell Cycle

: group of proteins that

control cascade of phosphorylation
pathways at various points in cell cycle

: surveillance
mechanism for ensuring orderly completion
of molecular events, sensing problems in
DNA replication, DNA repair, and
chromosome segregation. If problems
identified, progression to next phase of cell
cycle can be delayed or stopped.

Mechanism: control of cell cycle

Which cyclin ?

Which cyclin?

Cyclin-dependent kinase inhibitors

Cell Growth: molecular overview

Growth Factors or Cytokines
Bind to

Initiate

Promote
Changes in Gene Expression (up and down regulation)
Resulting in

Modes of Intercellular Signalling

Surface Receptors: 3 classes

Receptors with
intrinsic
_____________
_____________
_____________

____________________
(G protein-coupled)

Receptors
without
intrinsic
___________
___________
___________

Consequences of Receptor Activation

Intrinsic-kinase activity receptors:
Irreversible commitment of cell to enter
(proliferative response)

Receptors without intrinsic kinase activity

(cytokine superfamily):
Activation cytosolic kinases to mediate functional
response (not proliferative)

G-protein coupled (seven spanning) receptors:

Over 1500 receptors identified
Bind various ligands, producing specific intracellular
response

Signal Transduction by Tyrosine

Kinase Receptors
Growth factors: coming soon!
Clinical
application: if
mutant ras
protein is
permanently
fixed in active
GTP form, what
pathologic
process may
result?

Transcription Factors
Definition: intracellular proteins that regulate gene
expression, thereby controlling cell growth

Specific domains in transcription factors:

: permits factor to bind specifically to short

sequences of DNA
: allows factor to increase transcription of DNA

:allows factor to decrease transcription of DNA

Transcription factors known to be operative in malignant
neoplasms:
Growth promoting: c-MYC and c-JUN
Cell cycle inhibiting (tumor suppressor gene): p53

Growth Factors
Definition: proteins that bind to cell surface
receptors with
generating cascade response that signals
cell to enter S-phase (cell division).
These factors can also modulate cell
functions: locomotion, contractility,
differentiation, etc.

Major growth factors / effects

FACTOR
EGF = epidermal
TGF-a = transforming
VEGF=vascular endothelial
PDGF= platelet-derived

FGF= fibroblast
FGF-1=acidic
FGF-2=basic

EFFECTS
Mitogenic for epithelium & fibroblasts
Mitogenic for hepatocytes
Mitogenic for endothelial cells
Mitogenic for monocytes, fibroblasts,
smooth muscle cells; activates
neutrophils

Angiogenesis, wound repair (mitogenic

for both fibroblasts and keratinocytes)

Tissue Regeneration

Liver from living donor before

transplantation, outlining right
lobe to be used for grafting
into recipient

Liver of donor one week postpartial hepatectomy, showing

marked growth of left lobe
(compensatory hyperplasia)
without regrowth of right lobe.
Why didnt right lobe regrow also?

Extracellular matrix 1
Definition: macromolecules outside cells,
formed by local secretion and assembled into
network surrounding cells
Functions:
Sequester H2O for turgor; minerals for rigidity
Reservoir for growth factors
Scaffolding within which cells adhere, migrate, and
proliferate

Extracellular matrix (ECM) 2

Groups of macromolecules in ECM:
Fibrous structural proteins: 2 major families
are:
Adhesive glycoproteins
Gel proteins in intercellular junctions and cell
surfaces: proteoglycans & hyaluronic acid

Extracellular matrix (ECM) 3

Macromolecules of ECM assemble into
two types of organizational structure:

: fills spaces
between cells

: closely
associated with cell surfaces

Collagen: summary of major types

Skin (80%), bone (90%), tendons

Genetic deficiency of
type IV in:

Collagen synthesis

Nutrient required
for hydroxylation
of alpha chains:

Deficiency of this
nutrient causes
poor wound
healing in
disease called:

Inherited disorders
of collagen
synthesis, leading to
defective fibers:

Elastic Fibers
Definition: fibers capable of stretching and
recoiling to original size
Present in tissues requiring elasticity:
Skin, lung, uterus, ligaments, large blood vessels

Structure:
Central core protein:
Peripheral microfibrillary network:
Inherited defect synthesis of peripheral
microfibrillary network: abnormally weakened
elastic fibers. Syndrome?
Associated
Vascular
disease?

Adhesion molecules 1
Function:
attach cells to
ECM matrices;
2 glycoprotein
chains held
together by
disulfide bonds;
produced by
fibroblasts,
endothelial
cells, &
monocytes.
Name?

Adhesion molecules 2
Most abundant
glycoprotein in
basement
membranes; it
spans basal lamina
and binds to both
cell surfaces and
ECM components:

Adhesion molecules 3
Transmembrane
glycoproteins with
alpha and beta chains
that bind to
fibronectin, laminin,
& collagen. This
family of surface
receptors mediate
attachment of cell
membranes to ECM:
These also mediate
adhesion of which cell
type to endothelium?

Summary: interactions cell-ECM

Major EC structural protein:

Fig. 3-16, Pathologic Basis of Disease, 7th ed, Elsevier 2005

Overview: Repair after injury

ACUTE AND CHRONIC INFLAMMATION

Damage to parenchymal cells and interstitial framework

Regeneration of
parenchymal cells
whenever possible

Replacement of non-regenerated
damaged tissue by what?

Fibrosis (fibroplasia)
Four components:

: formation new blood

vessels

of fibroblasts into
damaged tissue

of extracellular matrix
Organization fibrous tissue =

Sequence of events in repair

24 hrs: proliferation of fibroblasts & endothelial cells

Within 3-5 days:

Little
mature
collagen

Proliferation
of young
fibroblasts

Permanent result
(weeks later)

New
capillaries

blue-staining collagen
(trichrome stain)

Angiogenesis
Definition: pre-existing vessels send out
capillary sprouts to form new vessels
cf. vasculogenesis: the primitive vascular
network established during embryogenesis
Clinical importance:
Repair post-inflammation
Formation collateral circulation (post-MI)
Support growth of neoplasms (therapeutic
implications)

Angiogenesis: 2 mechanisms

ECM proteins affecting angiogenesis

Integrins: formation and maintenance new vv.
Matrix proteins which destabilize cell-matrix
interactions, promoting angiogenesis:
Thrombospondin
SPARC
Tenascin C

Proteases that remodel matrix

Plasminogen activators
Matrix metalloproteinases

Fragment of collagen that inhibits endothelial

proliferation and angiogenesis, with therapeutic
application in neoplasia?

Fibrosis (fibroplasia)
Emigration and proliferation of fibroblasts at
injury site, triggered by multiple growth
factors produced by cells in granulation
tissue, most important of which is:
ECM deposition by fibroblasts: fibrillar
collagen synthesis enhanced by growth
factors and cytokines, thus converting
Into a

Tissue remodeling
Conversion granulation tissue into scar
involves changes in composition of ECM.

: enzymes which
degrade ECM components for remodeling.
These enzymes are dependent on
ions for activity.

Wound Healing
Healing by first intention

Healing by second intention

Summary: phases of wound healing

Wound tensile strength: 10% of normal at 7 days;

70-80% of normal at 3 months

Factors influencing wound healing

Local Factors

: most important single cause of delay

Mechanical: too early motion can delay
Foreign bodies: may impede or cause abscess
Location: speed of healing proportional to richness of
blood supply:
face > trunk > extremities
Type of wound: primary intention heals faster than
secondary intention

Factors influencing wound healing

Systemic factors:

: first of two most important

factors. Most important deficiencies (2):

: second of two most

important factors. Arterial or venous
insufficiency commonly delays healing.

: iatrogenic delay of healing

by blunting the normal inflammatory/repair
response

Pathologic complications of healing

: exaggeration normal
contraction of wound, resulting in deformity
(palms, soles, anterior thorax). Common
after burns.
Deficient granulation tissue/ scar formation:

: rupture of wound, usually

due to increased mechanical pressure or
inappropriate movement

: usually due to arterial

insufficiency caused by atherosclerosis; venous
stasis also can contribute.

Pathologic complications, 2
Excessive formation of repair components:

Excessive granulation tissue

Desmoid tumor (aggressive fibromatosis)
Best viewed as low grade neoplasm with stubborn tendency for
recurrences

Fibrosis: Summary

Overview: inflammation & repair

Conclusion
Physicians stand in wonder at the amazing
capacity of the body to restore itself after
injury, usually without loss of normal function.
This represents an advanced kind of
engineering and self-regulated maintenance
function that humbles human technology.