PATHOLOGY

TISSUE RENEWAL AND REPAIR:

Regeneration, Healing and Fibrosis

DR. R.S. Mc INTIRE

TISSUE RENEWAL & REPAIR

The repair of tissue damage can be broadly separated into 2

processes, regeneration & healing
REGENERATION
- results in restitution of lost tissues
HEALING
- may restore original structures but involves collagen deposition
& scar formation

TISSUE RENEWAL & REPAIR

Distinctions between Regeneration & Repair

REGENERATION
- refers to growth of cells & tissues to replace lost structures
- tissues w/ high proliferative capacity renew themselves continuously &
can regenerate after injury,
as long as the stem cells of
these tissues are not destroyed
- requires an intact connective tissue scaffold

TISSUE RENEWAL & REPAIR

HEALING
- is usually a tissue response
to a wound (commonly in the skin)
to inflammatory processes in internal organs
to cell necrosis in organs incapable of regeneration
- healing w/ scar formation occurs if the extracellular matrix (ECM)
framework is damage, causing alterations of the tissue architecture

*ECM acts as scaffold

Fig 3-1

TISSUE RENEWAL & REPAIR

CONTROL OF NORMAL CELL PROLIFERATION

GROWTH

AND TISSUE

In adult tissues, the size of cell populations is determined by the rates

of cell

proliferation

differentiation &

death by apoptosis

TISSUE RENEWAL & REPAIR

TISSUE RENEWAL & REPAIR

Cell proliferation can be stimulated by physiologic & pathologic

conditions
Physiologic
e.g. proliferation of endometrial cells under estrogen
stimulation during the menstrual cycle

Pathologic
e.g. uncontrolled growth of cancer cells

TISSUE RENEWAL & REPAIR

Tissue-Proliferative Activity
- the cell cycle consists of:

G1 (presynthetic) phase
S (DNA synthesis) phase
G2 (premitotic) phase

M (mitotic) phase
- Quiscent cells are in a physiologic state called G0

TISSUE RENEWAL & REPAIR

Fig 3-3
DNA synthesis

premitotic

mitotic

presynthetic

TISSUE PROLIFERATIVE ACTIVITY

TISSUE RENEWAL & REPAIR

The tissues of the body are divided into 3 groups on the basis of
their proliferative activity

1. Continuously dividing (Labile) tissues

2. Quiescent (Stable) tissues

3. Nondividing (Permanent) tissues

TISSUE RENEWAL & REPAIR

Continuously dividing (Labile) tissues

- the cells proliferate thro out life, replacing those that are destroyed
- in most of these tissues, mature cells are derived from stem cells

- w/c have an unlimited capacity to proliferate & whose progeny

may undergo various streams of differentiation

TISSUE RENEWAL & REPAIR

Quiescent (Stable) tissues

- cells normally have a low level of replication
- however, cells can undergo rapid division in response to stimuli
& are capable of reconstituting the tissue of origin

- considered to be in the G0 stage of the cell cycle but can be

stimulated to enter G1

TISSUE RENEWAL & REPAIR

Nondividing (Permanent) Tissues

- contain cells that have left the cell cycle
- cell cannot undergo mitotic division in post natal life

TISSUE RENEWAL & REPAIR

STEM CELLS
- stem cells are charac. by their prolonged self-renewal capacity & by
their asymmetric replication
Asymmetric replication
- a special property that exists w/n a whole population of stem
cells rather than in every single stem cell division

* thus w/n a group of stem cells

some self replicate & others differentiate

TISSUE RENEWAL & REPAIR

Asymmetric replication

TISSUE RENEWAL & REPAIR

STEM CELLS
Two Types:
1. Embryonic Stem Cells (ES)
2. Adult Stem Cells

TISSUE RENEWAL & REPAIR

Embryonic Stem Cells (ES)

- embryos contain pluripotent ES cells, w/c can give rise to all the
tissues of the human body

- such cells can be isolated from normal blastocysts

the structures formed at about the 32-cell stage

during embryonic development

TISSUE RENEWAL & REPAIR

TISSUE RENEWAL & REPAIR

TISSUE RENEWAL & REPAIR

Adult Stem Cells

- many tissues in adult contain reservoirs of stem cells,
are called adult stem cells

Tissue Stem Cells

- stem cells located outside the bone marrow

Hematopoietic stem cells (HSC)

- those w/n the bone marrow

w/c

TISSUE RENEWAL & REPAIR

Tissue Stem Cells

- have a more restricted differentiation capacity
- usually lineage-specific
- located in sites called niches, w/c differ among various tissues
Example:
1. Epidermal stem cells are located in the bulge area of the hair follicle

Niche - a bulge or
recess in a wall

TISSUE RENEWAL & REPAIR

Tissue Stem Cells

2. Intestinal stem cells are located at the base of a colon crypt

TISSUE RENEWAL & REPAIR

Tissue Stem Cells

3. Corneal stem cells are located in the limbus region,
the conjunctiva & the cornea

between

TISSUE RENEWAL & REPAIR

Bone Marrow
- contains: Hematopoietic stem cell (HSC)
Stromal cells capable of differentiation into
various lineages

TISSUE RENEWAL & REPAIR

Bone Marrow
Hematopoietic Stem cells

- generate all of the blood cells &

- can reconstitute the bone marrow after depletion
caused by disease or irradiation
Bone Marrow Stromal Cells

- depending on the tissue environment, can generate

chondrocytes
adipocytes
osteoblasts
myoblasts
endothelial cell precursors

TISSUE RENEWAL & REPAIR

GROWTH FACTORS
- in addition to stimulating cell proliferation, growth factors may also
have effects on

cell locomotion
differentiation

contractility
angiogenesis

w/c are involved in tissue regeneration and repair

Table 3-1

TISSUE RENEWAL & REPAIR

Signaling Mechanisms in Cell Growth

- all growth factors function by binding to specific receptors,
deliver signals to the target cells
- these signals have 2 general effects
1. they stimulate the transcription of many genes
2. these genes regulate the entry of the cells into the cell cycle

w/c

TISSUE RENEWAL & REPAIR

Signaling Mechanisms in Cell Growth

- the first event that initiates cell proliferation is the binding of a signaling
molecule, the ligand, to a specific cell receptor
- based on the source of the ligand & the location of its receptors (in the
same, adjacent, or distant cells) 3 general modes
of
signaling can be distinguished

Autocrine signaling
Paracrine signaling
Endocrine signaling

ligand link

TISSUE RENEWAL & REPAIR

Autocrine Signaling
- cells respond to the signaling molecules that they themselves secrete
- plays a role in

liver regeneration
proliferation of Ag-stimulated lymphocytes
growth of some tumors

TISSUE RENEWAL & REPAIR

Paracrine Signaling
- one cell type produces the ligand, w/c then acts on adjacent target cells that
express the appropriate receptors
- the responding cells are in close proximity to the ligand-producing cell and are
generally of different type

- common in connective tissue repair of healing wounds

- also necessary for hepatocyte replication during liver regeneration

TISSUE RENEWAL & REPAIR

Juxtacrine
a special type of paracrine signaling
- the signaling molecule is anchored in the cell membrane
&
binds a receptor in the plasma membrane of another cell
- the receptor-ligand interaction is dependent on & promotes cell-cell
adhesion

TISSUE RENEWAL & REPAIR

Endocrine Signaling

- hormones are synthesized by cells of endocrine organs &

- act on target cells distant from their site of synthesis,
usually carried by the blood

being

TISSUE RENEWAL & REPAIR

EXTRACELLULAR MATRIX (ECM) AND CELL-MATRIX INTERACTIONS

- cells grow, move, & differentiate in intimate contact w/

macromolecules outside the cell that constitute the ECM
the matrix critically influences these cell fxns
- the ECM is secreted locally & assembles into a network in the spaces
surrounding cells

TISSUE RENEWAL & REPAIR

Extracellular Matrix
serves many functions :
- they sequester water that provides turgor to soft tissues
minerals that give rigidity to skeletal tissues

&

- they fxn as reservoir for growth factors controlling cell proliferation

- they are important for cell-to-cell interactions & provides a substratum
for cells to adhere, migrate & proliferate
- synthesis & degradation of ECM accompanies morphogenesis, wound
healing and chronic fibrotic processes, as well as tumor invasion &
metastasis

TISSUE RENEWAL & REPAIR

Extracellular Matrix
these macromolecules are present in intercellular junctions
surfaces & may assemble into 2 general organizations

Interstitial matrix
Basement Membrane

& cell

TISSUE RENEWAL & REPAIR

Extracellular Matrix

TISSUE RENEWAL & REPAIR

REPAIR BY HEALING, SCAR FORMATION & FIBROSIS

Regeneration involve the restitution of tissue components
identical to those removed or killed

* by contrast, Healing is a fibroproliferative response that

patches rather than restore a tissue

TISSUE RENEWAL & REPAIR

Healing - is a complex but orderly phenomenon involving a

of processes

induction of inflammatory processes in response to initial injury,

of damaged & dead tissue

proliferation & migration of parenchymal & connective tissue cells

formation of new bld vessels (angiogenesis) & granulation tissue

synthesis of ECM proteins and collagen deposition

tissue remodeling

wound contraction

acquisition of wound strength

number
w/ removal

TISSUE RENEWAL & REPAIR

HEALING
- repair begins early in inflammation, sometimes as early as
24 hours after injury
- fibroblasts & vascular endothelial cells begin proliferating
to form a special type of tissue that is hallmark of healing
called granulation tissue

TISSUE RENEWAL & REPAIR

Granulation tissue
- the charac. histologic features are :

formation of new bld vessels (angiogenesis)

proliferation of fibroblasts

TISSUE RENEWAL & REPAIR

SCAR FORMATION
3 Processes that participate in the formation of a scar:
1. Emigration & proliferation of fibroblasts in the site of injury
2. Deposition of ECM
3. Tissue remodelling

TISSUE RENEWAL & REPAIR

CUTANEOUS WOUND HEALING

- generally divided into 3 phases

1. Inflammation

2. Granulation Tissue Formation and Reepithelialization

3. Wound contraction, ECM deposition and Remodeling
these phases overlap and their separation is
somewhat arbitrary

Arbitrary arrived at w/o allowing argument or objection

TISSUE RENEWAL & REPAIR

CUTANEOUS WOUND HEALING

TISSUE RENEWAL & REPAIR

CUTANEOUS WOUND HEALING

- skin wounds are classically described to heal by primary
secondary intension
- this distinction is based on the nature of the wound
than the healing process itself.

or
rather

TISSUE RENEWAL & REPAIR

CUTANEOUS WOUND HEALING

Healing by First Intention (Wounds with Opposed Edges)
- is the healing of a clean, uninfected surgical incision
by surgical sutures

approximated

- death of a limited no. of epithelial & connective tissue cells

as
well as disruption of epithelial basement membrane
continuity

TISSUE RENEWAL & REPAIR

Healing by Second Intention

- a form of healing when there is more extensive loss of cells and
tissues &
- when regeneration of parenchymal cells cannot completely
restore the original architecture

TISSUE RENEWAL & REPAIR

Healing by Second Intention

differs from primary intention in several respects:
large tissue defects generate larger fibrin clot & more

debris & exudate & inflammatory rxn

necrotic
is more intense

larger amounts of granulation tissue

presence of wound contraction

requires the action of myofibroblast

substantial scar formation and thinning of the epidermis

TISSUE RENEWAL & REPAIR

LOCAL & SYSTEMIC FACTORS

THAT INFLUENCE WOUND HEALING

TISSUE RENEWAL & REPAIR

TISSUE RENEWAL & REPAIR

TISSUE RENEWAL & REPAIR

COMPLICATIONS IN CUTANEOUS WOUND HEALING

- complications can arise from abnormalities in any of the basic
components of the repair process
- these are grouped into 3 general categories

1. deficient scar formation

2. excessive formation of the repair components
3. formation of contractures

TISSUE RENEWAL & REPAIR

Complications in Cutaneous Wound Healing

Inadequate formation of granulation tissue
- can lead to 2 types of complications

wound dehiscence
ulceration

Dehiscence or rupture of wound - is most common after

abdominal surgery & is due to abdominal pressure

Ulceration - occurs bec. of inadequate vascularization

during healing

TISSUE RENEWAL & REPAIR

Complications in Cutaneous Wound Healing

* Excessive formation of the repair components

Hypertrophic scar - excessive amounts of collagen may give

Keloid - scar tissue grows beyond the boundaries of the original

Exuberant granulation (proud flesh) - excessive amount of

a raised scar

wound & does not regress

granulation tissue w/c protrudes above the level

the surrounding skin & blocks re-epithelialization

Desmoids or Aggressive fibromatoses - these lie in the interface

bet. benign proliferation & malignant tumors

of

TISSUE RENEWAL & REPAIR

Complications in Cutaneous Wound Healing

* Formation of Contractures
Contraction - in the size of a wound is part of the N healing process
- exaggeration of this process is called a contracture
Contracture - results in deformities of the wound & surrounding
tissues

TISSUE RENEWAL & REPAIR

FIBROSIS
- occurs in chronic diseases
- in contrast to orderly wound healing, these diseases are assoc. w/
persistence of the initial stimuli for fibrosis or the devlpt of immune &
autoimmune rxns