Tissue Renewal,

Regeneration and Repair

Dr. Upik A. Miskad, PhD, SpPA

 Repair of tissue
• 1. Regeneration
– Replacement of injured cells by cells of the same
type
– Some times no residual trace
• 2. Fibroplasia/ Fibrosis
– Replacement by connective tissue
– Leave permanent scar
 Regeneration of epithelial cells
• Require the BM (basement membrane) for
complete regeneration.
• Involving cells migration, proliferation,
differentiation and cell-matrix interaction
Overview of healing responses after injury. Healing after acute injury can occur by
regeneration that restores normal tissue structure or by repair with scar formation.
Healing in chronic injury involves scar formation and fibrosis .
 TISSUE PROLIFERATIVE ACTIVITY

• The tissues of the body are divided into 3

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).
1. Continuosly dividing cells/ labile cells
• Proliferate throughout life, replacing those that
are destroyed.
• These tissues 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, and
cells of the bone marrow and hematopoietic tissues.
 2. Quiescent/ Stable cells
• have a low level of replication; can undergo rapid division in
response to stimuli and are thus capable of reconstituting the
tissue of origin.
• Consist of:
– the parenchymal cells of liver, kidneys, and pancreas
– mesenchymal cells such as fibroblasts and smooth muscle,
chondrocytes, and osteocytes ;
– vascular endothelial cells; and
– lymphocytes and other leukocytes.

– EXAMPLE: the ability of the liver to regenerate after partial

hepatectomy and after acute chemical injury.
– Fibroblasts in particular can proliferate extensively, as in healing
processes and fibrosis.
 3. Nondividing /permanent cells
Contain cells that have left the cell cycle and
cannot undergo mitotic division in postnatal life.
Include: neurons and skeletal and cardiac muscle
cells
If neurons in the central nervous system are destroyed, the
tissue is generally replaced by the glial cells. Recent
research : limited neurogenesis from stem cells may occur
in adult brains.
Cardiac muscle has very limited, if any, regenerative capacity,
and a large injury to the heart muscle, as may occur in
myocardial infarction, is followed by scar formation.
 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 .
Mechanism of regulating cells population
Cell Cycle & Regulation of Cell Replication

• The replication of cells is stimulated by growth factors or

by signaling from ECM components through integrins.
• The cell cycle consists of
– G1 (presynthetic),
– S (DNA synthesis),
– G2 (premitotic), and
– M (mitotic) phases.

The cells that have not entered the cell cycle are in the G0 state.
The cell cycle has multiple controls, particularly during the
transition between the G1 and S phases.
 GROWTH FACTORS

• The proliferation of many cell types is driven by polypeptides

known as growth factors.

• Growth factors, may promote cell survival, locomotion,

contractility, differentiation, and angiogenesis.

• All growth factors function as ligands that bind to specific

receptors, which deliver signals to the target cells.

• These signals stimulate the transcription of genes that may be

silent in resting cells, including genes that control cell cycle entry
and progression..
 SIGNALING MECHANISMS IN CELL
GROWTH
• According to the source of the ligand and the location of its
receptors
• Autocrine signaling: Cells respond to the signaling molecules
that they themselves secrete, thus establishing an autocrine
loop. Tumors frequently overproduce growth factors and their
receptors, thus stimulating their own proliferation through an
autocrine loop.
• Paracrine signaling: One cell type produces the ligand, which
then acts on adjacent target cells that express the appropriate
receptor. The responding cells are in close proximity to the
ligand-producing cell and are generally of a different type.
• Endocrine signaling: Hormones synthesized by cells of
endocrine organs act on target cells distant from their site of
synthesis, being usually carried by the blood.
 Receptors and Signal Transduction
Pathways
• The binding of a ligand to its receptor
triggers a series of events by which
extracellular signals are transduced into the
cell resulting in changes in gene expression.
• Ligand: molecule that bind to the receptor.
• Receptors : are generally located on the
surface of the target cell but can also be
found in the cytoplasm or nucleus.
Overview of the main types of cell surface receptors and their principal signal transduction
pathways. Shown are receptors with intrinsic tyrosine kinase activity, seven
transmembrane G protein–coupled receptors, and receptors without intrinsic tyrosine
kinase activity. cAMP, cyclic adenosine monophosphate: IP3, inositol triphosphate; JAK, Janus kinase; MAP
kinase, mitogen-activated protein kinase; PI3 kinase, phosphatidylinositol 3-kinase; PKB, protein kinase B, also known
as Akt; PLC-γ, phospholipase C gamma; STATs, signal transducers and activators of transcription.
 RECEPTORS
• 1. Receptors with intrinsic tyrosine kinase activity.
The ligands for receptors with tyrosine kinase activity
include most growth factors such as EGF, TGF-α, HGF,
PDGF, VEGF, FGF, c-KIT ligand, and insulin.
• 2. Receptors lacking intrinsic tyrosine kinase activity
that recruit kinases. Ligands for these receptors
include many cytokines, such as IL-2, IL-3, and other
interleukins; interferons α, β, and γ; erythropoietin;
granulocyte colony-stimulating factor; growth
hormone; and prolactin.
• 3. G protein–coupled receptors. These receptors
transmit signals into the cell through trimeric
GTP-binding proteins (G proteins).

• 4. Steroid hormone receptors. These receptors

are generally located in the nucleus and function
as ligand-dependent transcription factors. The
ligands diffuse through the cell membrane and
bind the inactive receptors, causing their
activation.
Signaling from tyrosine kinase receptors. Binding of the growth factor (ligand) causes receptor dimerization and
autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins (e.g., GRB2 and SOS) couples
the receptor to inactive RAS. Cycling of RAS between its inactive and active forms is regulated by GAP. Activated RAS
interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates a
component of the MAP kinase signaling pathway, MEK (also known as MAP kinase kinase or MKK), which then
phosphorylates ERK (MAP kinase or MK). Activated MAP kinase phosphorylates other cytoplasmic proteins and
nuclear transcription factors, generating cellular responses. The phosphorylated tyrosine kinase receptor can also bind
other components, such as phosphatidyl 3-kinase (PI3 kinase), which activates other signaling systems.
 Transcription Factors

• Many of the signal transduction systems used by growth

factors transfer information to the nucleus and modulate
gene transcription through the activity of transcription
factors.

• Transcription factors have a modular design and contain

domains for DNA binding and for transcriptional
regulation. The DNA-binding domain permits binding to
short sequence motifs of DNA. The transactivating domain
stimulates transcription of the adjacent gene.

• Growth factors induce the synthesis or activity of

transcription factors.
 Extracellular Matrix (ECM) and Cell-
Matrix Interactions
• ECM is a macromolecule complex which
regulates the growth, proliferation,
movement, and differentiation of the cells
living within it.
• It is constantly remodeling, and its synthesis
and degradation accompanies
morphogenesis, regeneration, wound
healing, chronic fibrotic processes, tumor
invasion, and metastasis.
 Extracellular Matrix
• ECM functions :
• • Mechanical support for cell anchorage and cell migration, and
maintenance of cell polarity
• • Control of cell growth. ECM components can regulate cell
proliferation by signaling through cellular receptors of the integrin
family.
• • Maintenance of cell differentiation. The type of ECM proteins can
affect the degree of differentiation of the cells in the tissue, also acting
largely via cell surface integrins.
• • Scaffolding for tissue renewal. The maintenance of normal tissue
structure requires a basement membrane or stromal scaffold.
• • Establishment of tissue microenvironments. Basement membrane
acts as a boundary between epithelium and underlying connective tissue
and also forms part of the filtration apparatus in the kidney.
• • Storage and presentation of regulatory molecules. For example,
growth factors like FGF and HGF are secreted and stored in the ECM in
some tissues. This allows the rapid deployment of growth factors after
local injury, or during regeneration.
 ECM
• The ECM is composed of three groups of
macromolecules:
– fibrous structural proteins, such as collagens and
elastins that provide tensile strength and recoil;
– adhesive glycoproteins that connect the matrix
elements to one another and to cells; and
– proteoglycans and hyaluronan that provide
resilience (pegas) and lubrication.

.
 ECM
Two basic forms of ECM:
1. interstitial matrix
2. basement membranes.

The interstitial matrix is found in spaces between

epithelial, endothelial, and smooth muscle cells, as
well as in connective tissue. It consists mostly of
fibrillar and nonfibrillar collagen, elastin, fibronectin,
proteoglycans, and hyaluronan.
Basement membranes are closely associated with cell
surfaces, and consist of nonfibrillar collagen (mostly
type IV), laminin, heparin sulfate, and proteoglycans
 COLLAGEN
• COLLAGEN
• Collagen is the most common protein providing
the extracellular framework for all multicellular
organisms.
• Currently, 27 different types of collagens
encoded by 41 genes dispersed on at least 14
chromosomes are known.
• Each collagen is composed of three chains that
form a trimer in the shape of a triple helix.
 ELASTIN, FIBRILLIN, AND ELASTIC
FIBERS
• Tissues such as blood vessels, skin, uterus, and lung
require elasticity for their function.
• Proteins of the collagen family provide tensile strength,
but the ability of these tissues to expand and recoil
(compliance) depends on the elastic fibers. These fibers
can stretch and then return to their original size after
release of the tension. Morphologically, elastic fibers
consist of a central core made of elastin, surrounded by a
peripheral network of microfibrils.
• Substantial amounts of elastin are found in the walls of
large blood vessels, such as the aorta, and in the uterus,
skin, and ligaments.
 CELL ADHESION PROTEINS

• Most adhesion proteins, also called CAMs

(cell adhesion molecules), can be classified
into four main families:
1. immunoglobulin family CAMs, c
2. adherins,
3. integrins, and
4. selectins.
 CELL ADHESION PROTEINS

• Integrins bind to ECM proteins such as fibronectin, laminin, and

osteopontin providing a connection between cells and ECM, and
also to adhesive proteins in other cells, establishing cell-to-cell
contact.
• Fibronectin is a large protein that binds to many molecules, such
as collagen, fibrin, proteoglycans, and cell surface receptors. It
consists of two glycoprotein chains, held together by disulfide
bonds.
• Laminin is the most abundant glycoprotein in the basement
membrane and has binding domains for both ECM and cell surface
receptors. In the basement membrane, polymers of laminin and
collagen type IV form tightly bound networks.
Thanks for attention