Inflammation

and Repair - 8

Dr.CSBR.Prasad, M.D.

v3-CSBRP-May-2012

Tissue renewal

Regeneration

and

Repair

v3-CSBRP-May-2012

Regeneration

Regeneration refers to the proliferation of

cells and tissues to replace lost structures

Whole organs and complex tissues rarely

regenerate after injury

Exceptions are liver, epithelia of GIT, Skin,

Hemopoietic tissue

Compensatory growth Vs Regeneration

v3-CSBRP-May-2012

Repair

Repair is a healing process

It’s a combination of regeneration and scar formation

v3-CSBRP-May-2012

Repair

Tissue repair depends on:

the ability of the tissue to

regenerate and

the extent of the injury

v3-CSBRP-May-2012

Repair

Chronic inflammation > growth factors and cytokines > Scar

FIBROSIS is used to describe the extensive deposition of collagen

v3-CSBRP-May-2012

Repair

ECM components are essential for wound healing: Provide the framework for cell migration

Facilitate Angiogenesis

Cells in the ECM produce growth factors

v3-CSBRP-May-2012

Repair

Although repair is a healing process,

it may cause tissue dysfunction

v3-CSBRP-May-2012

Repair

Examples:

• AS

• Healed MI

• Cirrhosis

• Contractures

• Corneal opacities

• Pulmonary fibrosis

• Bronchiectasis

• Intestinal strictures

• Adhesions after

surgery

• Ankylosis

• Cranial nerve palsies

after TB-meningitis

Although repair is a healing process, it may cause tissue dysfunction

v3-CSBRP-May-2012

Cirrhosis of liver v3-CSBRP-May-2012

Pulmonary fibrosis v3-CSBRP-May-2012

v3-CSBRP-May-2012

v3-CSBRP-May-2012

Basal Meningitis - TB v3-CSBRP-May-2012

6th left cranial nerve plasy v3-CSBRP-May-2012

v3-CSBRP-May-2012

v3-CSBRP-May-2012

v3-CSBRP-May-2012

v3-CSBRP-May-2012

Ocular Herpes v3-CSBRP-May-2012

v3-CSBRP-May-2012

Understanding the mechanisms of regeneration

and repair requires:

•knowledge of the control of cell proliferation

•signal transduction pathways, and

•functions of ECM components

v3-CSBRP-May-2012

Principles of cell proliferation

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, and

death by apoptosis

• Cell proliferation can be stimulated by

physiologic and pathologic conditions

v3-CSBRP-May-2012

Principles of cell proliferation

Physiological:

EM to Estrogen

Thyroid to TSH,

pregnancy

Pathological:

• NPH to

dihydrotestosterone

• Nodular goitres to

TSH

Control of Normal Cell Proliferation and Tissue Growth

Cell proliferation can be stimulated by physiologic

and pathologic conditions

v3-CSBRP-May-2012

Why thyroid enlarges in

pregnancy?

α-chain of HCG is identical to

the α-chain of TSH

v3-CSBRP-May-2012

Principles of cell proliferation

Cell proliferation is largely controlled by signals

(soluble or contact-dependent) from the

microenvironment that either stimulate or inhibit

proliferation

An excess of stimulators or a deficiency of

inhibitors leads to net growth and, in the case of

cancer, uncontrolled growth

v3-CSBRP-May-2012

TISSUE PROLIFERATIVE

ACTIVITY

The tissues of the body are divided into

three groups on the basis of the

proliferative activity of their cells:

1. Continuously dividing (labile tissues)

2. Quiescent (stable tissues) and

3. Nondividing (permanent tissues)

v3-CSBRP-May-2012

TISSUE PROLIFERATIVE ACTIVITY

1. Continuously dividing (labile tissues)

Cells proliferate throughout life, replacing those that are destroyed

Examples include:

Surface epithelia, such as stratified squamous epithelia of the skin, oral cavity, vagina, and cervix; the lining mucosa of all the excretory ducts of the glands of the body (e.g., salivary glands, pancreas, biliary tract)

The columnar epithelium of the GI tract and uterus; the transitional epithelium of the urinary tract

Cells of the bone marrow and hematopoietic tissues

In most of these tissues mature cells are derived from adult stem cells, which have a tremendous capacity to proliferate

v3-CSBRP-May-2012

TISSUE PROLIFERATIVE ACTIVITY

1. Continuously dividing (labile tissues)

2. Quiescent (stable tissues)

Have a low level of replication

Can undergo rapid division in response to stimuli

Examples:

Parenchymal cells of liver, kidneys, and pancreas

Mesenchymal cells such as fibroblasts and smooth muscle

Vascular endothelial cells and

Lymphocytes and other leukocytes v3-CSBRP-May-2012

TISSUE PROLIFERATIVE ACTIVITY

1. Continuously dividing (labile tissues)

2. Quiescent (stable tissues)

3. Nondividing (permanent tissues)

Cells that have left the cell cycle

Cannot undergo mitotic division

Examples:

• Neurons

• Skeletal and

• Cardiac muscle cells

Gliosis

Cardiac muscle has very limited regenerative capacity v3-CSBRP-May-2012

v3-CSBRP-May-2012

v3-CSBRP-May-2012

Role of the extracellular

matrix in regeneration

and repair:

Liver regeneration with

restoration of normal

tissue after injury requires

an intact cellular matrix. If

the matrix is damaged the

injury is repaired by

fibrous tissue deposition

and scar formation

STEM CELLS

• Stem cells are characterized by their self-

renewal properties and by their capacity to

generate differentiated cell lineages

v3-CSBRP-May-2012

Stem cells

Maintainance of stem cells is achieved by two mechanisms:

1. Obligatory asymmetric replication

with each cell division, one of the daughter cells retains its self-renewing capacity while the other enters a differentiation pathway

2. Stochastic differentiation:

cell division may generate either two self-renewing stem cells or two cells that will differentiate

v3-CSBRP-May-2012

v3-CSBRP-May-2012

Terms

o Pluripotent stem cells: can generate all tissues of the body

o Multipotent stem cells: which have more restricted developmental potential, and eventually produce differentiated cells from the three embryonic layers

o Transdifferentiation: indicates a change in the lineage commitment of a stem cell

o Adult stem cells or somatic stem cells: have a more restricted capacity to generate different cell types have been identified in many tissues

o Induced pluripotent stem cells: differentiated cells of humans can be reprogrammed into pluripotent cells, similar to ES cells, by the transduction of genes encoding ES cell transcription factor

v3-CSBRP-May-2012

v3-CSBRP-May-2012

Reprogramming of Differentiated Cells:

Induced Pluripotent Stem Cells

• Transfer the nucleus to an enucleated oocyte.

• The oocytes implanted into a surrogate mother

• This can generate cloned embryos that develop into complete animals

• This procedure, known as reproductive cloning,

• therapeutic cloning:In this technique the nucleus of a skin fibroblast from a patient is introduced into an enucleated human oocyte to generate ES cells, which are kept in culture, and then induced to differentiate into various cell types.

• These cells are inefficient and often inaccurate. One of the main reasons for the inaccuracy is the deficiency in histone methylation in reprogrammed ES cells, which results in improper gene expression.

v3-CSBRP-May-2012

v3-CSBRP-May-2012

LIVER REGENERATION

Hepatocyte proliferation in the regenerating

liver is triggered by the combined actions of

cytokines and polypeptide growth factors

– Priming phase – TNF, IL-6 & C – system

– DNA synthesis – HGF, TGFα, and HB-EGF

– Adjuvants - Norepinephrine, serotonin, insulin,

thyroxin and growth hormone

v3-CSBRP-May-2012

• Individual hepatocytes replicate once or twice during regeneration and then return to quiescence

• Growth inhibitors, such as TGF-β and activins, may be involved in terminating hepatocyte replication

• Intrahepatic stem or progenitor cells do not play a role in the compensatory growth that occurs after partial hepatectomy

• Endothelial cells and other nonparenchymal cells in the regenerating liver may originate from bone marrow precursors

v3-CSBRP-May-2012

v3-CSBRP-May-2012

Extracellular Matrix and

Cell-Matrix Interactions

Tissue repair and regeneration depends on:

• Cytokines

• Interactions between cells & ECM

The ECM regulates the growth, proliferation,

movement, and differentiation of the cells

living within it

v3-CSBRP-May-2012

ECM - various functions

• Mechanical support

• Control of cell growth

• Maintenance of cell differentiation

• Scaffolding for tissue renewal

• Establishment of tissue

microenvironments

• Storage and presentation of regulatory

molecules

v3-CSBRP-May-2012

ECM - Composition

The ECM is composed of three groups of

macromolecules:

Fibrous structural proteins - provide tensile

strength

Adhesive glycoproteins: connect the

matrix elements to one another and to

cells

Proteoglycans and hyaluronan - resilience

v3-CSBRP-May-2012

Mechanisms by which ECM components and growth

factors interact and activate signaling pathways

v3-CSBRP-May-2012

Angiogenesis by mobilization of endothelial precursor

cells (EPCs) from the bone marrow and from

preexisting vessels (capillary growth)

v3-CSBRP-May-2012

Main components of the

extracellular matrix (ECM)

v3-CSBRP-May-2012

Healing by Repair,

Scar Formation and Fibrosis

v3-CSBRP-May-2012

Healing by Repair,

Scar Formation and Fibrosis

Repair occurs by fibrosis & scar formation

when:

• There is loss of parenchyma & frame work

Here lost tissue will be replaced by collagen

v3-CSBRP-May-2012

Repair by connective tissue deposition

includes the following basic features:

• Inflammation

• Angiogenesis

• Migration and proliferation of fibroblasts

• Scar formation

• Connective tissue remodeling

v3-CSBRP-May-2012

Angiogenesis

During embryonic development:

Vasculogenesis:

• Angioblasts

• Hemangioblasts

In adults:

Angiogenesis or Neovascularization

• Endothelium of adjacent pre-existing vessels

• BM endothelial progenitor cells (EPCs) v3-CSBRP-May-2012

Angiogenesis

Angiogenesis from Preexisting Vessels:

• Vasodilation

• Degradation of the BM

• Migration of endothelial cells

• Proliferation of endothelial cells

• Maturation of endothelial cells

• Recruitment of periendothelial cells

v3-CSBRP-May-2012

Angiogenesis

Angiogenesis from Endothelial Precursor Cells (EPCs):

• EPCs can be recruited from the bone marrow

• The number of circulating EPCs increases greatly in patients with ischemic conditions

• Examples:

– Re-endothelization of vascular implants

– Neovascularization of ischemic organs

– Neovascularization of cutaneous wounds

– Neovascularization of tumors v3-CSBRP-May-2012

Angiogenesis

Growth Factors and Receptors Involved in Angiogenesis

VEGF is the most important growth factor in adult tissues

Newly formed vessels are fragile and need to become “stabilized” – Pericytes

– Smooth muscle cells

Factors that participate in the stabilization process: – Angiopoietins 1 and 2

– PDGF, and

– TGF-β

v3-CSBRP-May-2012

E N D

v3-CSBRP-May-2012

v3-CSBRP-May-2012