3 PT LEC - Tissue Renewal & Repair- Regeneration, Healing, & Fibrosis

TISSUE RENEWAL AND REPAIR:

Regeneration, Healing and Fibrosis

PATHOLOGY

DR. R.S. Mc INTIRE

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


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

CONTROL OF NORMAL CELL PROLIFERATION AND TISSUE GROWTH

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

proliferation

differentiation &

death by apoptosis


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-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


Fig 3-3

TISSUE PROLIFERATIVE ACTIVITY


presynthetic

DNA synthesis premitotic

mitotic

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


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


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


Nondividing (Permanent) Tissues

- contain cells that have left the cell cycle

- cell cannot undergo mitotic division in post natal life


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



Asymmetric replication

STEM CELLS

Two Types:

1. Embryonic Stem Cells (ES)

2. Adult Stem Cells


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

Adult Stem Cells

- many tissues in adult contain reservoirs of stem cells, w/c 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


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 Stem Cells

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


Tissue Stem Cells

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


Bone Marrow

- contains: Hematopoietic stem cell (HSC)

Stromal cells capable of differentiation into various lineages


Bone Marrow Stromal Cells

- depending on the tissue environment, can generate

chondrocytes adipocytes

osteoblasts myoblasts

endothelial cell precursors


Hematopoietic Stem cells

- generate all of the blood cells &

- can reconstitute the bone marrow after depletion

caused by disease or irradiation

Bone Marrow

GROWTH FACTORS

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

cell locomotion contractility

differentiation angiogenesis

w/c are involved in tissue regeneration and repair


Table 3-1

Signaling Mechanisms in Cell Growth

- all growth factors function by binding to specific receptors, w/c 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


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

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

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

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


Endocrine Signaling

- hormones are synthesized by cells of endocrine organs &

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


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


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



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

Interstitial matrix

Basement Membrane


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


Healing - is a complex but orderly phenomenon involving a number of processes

induction of inflammatory processes in response to initial injury, w/ removal 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



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

Granulation tissue

- the charac. histologic features are :

formation of new bld vessels (angiogenesis)

proliferation of fibroblasts


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


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


- skin wounds are classically described to heal by primary or secondary intension

- this distinction is based on the nature of the wound rather than the healing process itself.



Healing by First Intention (Wounds with Opposed Edges)

- is the healing of a clean, uninfected surgical incision approximated by surgical sutures

- death of a limited no. of epithelial & connective tissue cells as well as disruption of epithelial basement membrane continuity


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


large tissue defects generate larger fibrin clot & more necrotic debris & exudate & inflammatory rxn 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


Healing by Second Intention

differs from primary intention in several respects:

LOCAL & SYSTEMIC FACTORS

THAT INFLUENCE WOUND HEALING


TIS

SU

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EN

EW

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REP

AIR


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


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



* Excessive formation of the repair components

Hypertrophic scar - excessive amounts of collagen may give a raised scar

Keloid - scar tissue grows beyond the boundaries of the original wound & does not regress

Exuberant granulation (proud flesh) - excessive amount of granulation tissue w/c protrudes above the level of

the surrounding skin & blocks re-epithelialization

Desmoids or Aggressive fibromatoses - these lie in the interface bet. benign proliferation & malignant tumors



* 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


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


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3 PT LEC - Tissue Renewal & Repair- Regeneration, Healing, & Fibrosis