3. 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
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4. Repair
Repair is a healing process
It’s a combination of regeneration and
scar formation
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5. Repair
Tissue repair depends on:
the ability of the tissue to
regenerate and
the extent of the injury
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6. Repair
Chronic inflammation > growth factors
and cytokines > Scar
FIBROSIS is used to describe the
extensive deposition of collagen
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7. Repair
ECM components are essential for wound
healing:
Provide the framework for cell migration
Facilitate Angiogenesis
Cells in the ECM produce growth factors
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9. Repair
Although repair is a healing process, it may cause
tissue dysfunction
Examples: • Intestinal strictures
• AS • Adhesions after
• Healed MI surgery
• Cirrhosis • Ankylosis
• Contractures • Cranial nerve palsies
after TB-meningitis
• Corneal opacities
• Pulmonary fibrosis
• Bronchiectasis
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22. Understanding the mechanisms of regeneration
and repair requires:
•knowledge of the control of cell proliferation
•signal transduction pathways, and
•functions of ECM components
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23. 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
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24. Principles of cell proliferation
Control of Normal Cell Proliferation and Tissue Growth
Cell proliferation can be stimulated by physiologic
and pathologic conditions
Physiological: Pathological:
EM to Estrogen • NPH to
Thyroid to TSH, dihydrotestosterone
pregnancy • Nodular goitres to
TSH
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25. Why thyroid enlarges in
pregnancy?
α-chain of HCG is identical to
the α-chain of TSH
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26. 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
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27. 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)
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28. 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
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29. 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
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30. 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
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32. 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
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33. STEM CELLS
• Stem cells are characterized by their self-
renewal properties and by their capacity to
generate differentiated cell lineages
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34. 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
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36. 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
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38. 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.
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40. 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
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41. • 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
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43. 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
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44. 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
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45. 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
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46. Mechanisms by which ECM components and growth
factors interact and activate signaling pathways
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47. Angiogenesis by mobilization of endothelial precursor
cells (EPCs) from the bone marrow and from
preexisting vessels (capillary growth)
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50. 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
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51. Repair by connective tissue deposition
includes the following basic features:
• Inflammation
• Angiogenesis
• Migration and proliferation of fibroblasts
• Scar formation
• Connective tissue remodeling
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52. Angiogenesis
During embryonic development:
Vasculogenesis:
• Angioblasts
• Hemangioblasts
In adults:
Angiogenesis or Neovascularization
• Endothelium of adjacent pre-existing vessels
• BM endothelial progenitor cells (EPCs)
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53. 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
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54. 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
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55. 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
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