Cell and tissue regeneration involves cell proliferation driven by growth factors and the development of mature cells from stem cells. There are three types of tissues based on their proliferative capacity: labile tissues which continuously divide, stable tissues which have limited proliferation, and permanent tissues which do not regenerate. Liver regeneration is remarkable, with up to 90% resection compensated by hepatocyte proliferation induced by cytokines and growth factors. When hepatocytes are impaired, liver progenitor cells contribute to repopulation.

1. Cell and Tissue
Regeneration
Dr IMRANA

2. The regeneration of injured cells and tissues
involves
Cell proliferation which is driven by growth
factors and is critically dependent on the
integrity of the extracellular matrix, and by the
development of mature cells from stem cells.

3. Cell Proliferation: Signals and
Control Mechanisms
 Several cell types proliferate during tissue repair.
Remnants of the injured tissue (which attempt to
restore normal structure)
Vascular endothelial cells (to create new vessels that
provide the nutrients needed for the repair process),
Fibroblasts (the source of the fibrous tissue that
forms the scar to fill defects that cannot be corrected
by regeneration).

4. The ability of tissues to repair themselves is
determined, in part, by their intrinsic
proliferative capacity.
Tissues of the body are divided into three
groups.
Labile (continuously dividing) tissues
Stable tissues
Permanent tissues

5. Labile (continuously dividing)
tissues.
Continuously being lost and replaced by maturation
from tissue stem cells and by proliferation of mature
cells.
-Hematopoietic cells in the bone marrow
-Majority of surface epithelia
Stratified squamous epithelia of the skin, oral cavity,
vagina, and cervix; the cuboidal epithelia of the ducts
draining exocrine organs (e.g. salivary glands,
pancreas, biliary tract)
Columnar epithelium of the gastrointestinal tract,
uterus, and fallopian tubes; and the transitional
epithelium of the urinary tract.

6.  These tissues can readily regenerate after
injury as long as the pool of stem cells is
preserved.

7. Stable tissues
Cells of these tissues are quiescent (in the G0 stage
of the cell cycle) and have only minimal proliferative
activity in their normal state
These cells are capable of dividing in response to
injury or loss of tissue mass.
Stable cells constitute the parenchyma of most solid
tissues, such as liver, kidney, and pancreas.
Include endothelial cells, fibroblasts, and smooth
muscle cells; the proliferation of these cells is
particularly important in wound healing.

8.  With the exception of liver, stable tissues have
a limited capacity to regenerate after injury.

9. Permanent tissues
The cells of these tissues are considered to be terminally
differentiated and nonproliferative in postnatal life.
Majority of neurons and cardiac muscle cells.
Thus, injury to the brain or heart is irreversible and results in a
scar, because neurons and cardiac myocytes cannot regenerate.
Limited stem cell replication and differentiation occur
in some areas of the adult brain, and there is some evidence
that heart muscle cells may proliferate after myocardial
necrosis. Nevertheless, whatever proliferative capacity may exist
in these tissues, it is insufficient to produce tissue regeneration
after injury.

10. Skeletal muscle is usually classified as a
permanent tissue, but satellite cells attached to
the endomysial sheath provide some
regenerative capacity for muscle. In permanent
tissues,repair is typically dominated by scar
formation.

11. Cell proliferation is driven by
signals
Provided by growth factors and from the
extracellular matrix
Growth factors are typically produced by cells
near the site of damage
Most important sources of these growth factors
are macrophages
epithelial and stromal cells also produce some of
these factors.

12.  Several growth factors bind to ECM proteins and
are displayed at high concentrations
 All growth factors activate signaling pathways
that ultimately induce the production of proteins that
are involved in driving cells through the cell cycle and
other proteins that release blocks on the cell cycle
(checkpoints)

13.  In addition to responding to growth factors, cells
use integrins to bind to ECM proteins, and signals
from the integrins can also stimulate cell
proliferation.
 In the process of regeneration, proliferation of
residual cells is supplemented by development of
mature cells from stem cells.
 In adults, the most important stem cells
for regeneration after injury are tissue stem cells
(stem cells live in specialized niches)

14.  Injury triggers signals in these niches that activate
quiescent stem cells to proliferate and differentiate into
mature cells that repopulate the injured tissue.

15. Mechanisms of Tissue
Regeneration
 Importance of regeneration in the replacement of injured
tissues varies in different types of tissues and with the
severity of injury.
 In labile tissues; injured cells are rapidly replaced by
proliferation of residual cells and differentiation of tissue
stem cells provided the underlying basement membrane
is intact. The growth factors involved in these processes
are not defined. Loss of blood cells is corrected by
proliferation of hematopoietic stem cells in the bone
marrow and other tissues, driven by growth factors
called colony-stimulating factors (CSFs), which are
produced in response to the reduced numbers of blood
cells.

16.  Tissue regeneration can occur in parenchymal
organs with stable cell populations, but with
the exception of the liver, this is usually a
limited process.
 Pancreas, adrenal, thyroid, and lung have
some regenerative capacity. The surgical
removal of a kidney elicits in the remaining
kidney a compensatory response that
consists of both hypertrophy and hyperplasia
of proximal duct cells.

17.  The mechanisms underlying this response
are not understood, but likely involve local
production of growth factors and interactions of
cells with the ECM.
 The extraordinary capacity of the liver to
regenerate has made it a valuable model for
studying this process, as described below.

18.  Restoration of normal tissue structure can
occur only if the residual tissue is structurally
intact, as after partial surgical resection.
 If the entire tissue is damaged by infection or
inflammation, regeneration is incomplete and
is accompanied by scarring.

19. Extensive destruction of the liver with collapse of
the reticulin framework, as occurs in a liver
abscess, leads to scar formation even though
the remaining liver cells have the capacity to
regenerate.

20. Liver Regeneration
 The human liver has a remarkable capacity to
regenerate, as demonstrated by its growth
after partial hepatectomy, which may be
performed for tumor resection or for living
donor hepatic transplantation.

21. ZEUS
 The mythologic image of liver regeneration is
the regrowth of the liver of Prometheus, which
was eaten every day by an eagle sent by
Zeus as punishment for stealing the secret of
fire, and grew back overnight. The reality,
although less dramatic, is still quite
impressive.

22.  Regeneration of the liver occurs by two major
mechanisms:proliferation of remaining
hepatocytes and repopulation from progenitor
cells

23. Proliferation of hepatocytes
In humans, resection of up to 90% of the liver
can be corrected by proliferation of the residual
hepatocytes.
This classic model of tissue regeneration has
been used experimentally to study the initiation
and control of the process.

24.  Hepatocyte proliferation in the regenerating
liver is triggered by the combined actions of
cytokines and polypeptide growth factors.

25. Priming, phase,
 Cytokines such as IL-6 are produced mainly
by Kupffer cells and act on hepatocytes to
make the parenchymal cells competent to
receive and respond to growth factor signals.

26. Growth factor
 Growth factors such as HGF and TGF-α,
produced by many cell types, act on primed
hepatocytes to stimulate cell metabolism and
entry of the cells into the cell cycle.

27. Hepatocytes are quiescent cells, it takes them
several hours to enter the cell cycle, progress from
G0 to G1, and reach the S phase of DNA
replication. Almost all hepatocytes replicate during
liver regeneration after partial hepatectomy.

28.  The wave of hepatocyte replication is followed by
replication of nonparenchymal cells (Kupffer
cells, endothelial cells, and stellate cells).
 During the phase of hepatocyte replication, more
than 70 genes are activated; these include genes
encoding transcription factors, cell cycle
regulators, regulators of energy metabolism, and
many others.

29. Termination, phase
 Hepatocytes return to quiescence.
Antiproliferative cytokines of the TGF-β family
are likely involved.

30. Liver regeneration from
progenitor cells
 In situations where the proliferative capacity
of hepatocytes is impaired, such as after
chronic liver injury or inflammation, progenitor
cells in the liver contribute to repopulation.

31.  In rodents, these progenitor cells have been
called oval cells because of the shape of their
nuclei. Some of these progenitor cells reside
in specialized niches called canals of Hering,
where bile canaliculi connect with larger bile
ducts.

32. References
Robbins & Cotran Pathologic Basis of Disease,
9e (Robbins Pathology) 9th Edition
by Vinay Kumar MBBS MD FRCPath (Author),
Abul K. Abbas MBBS (Author), Jon C. Aster MD
PhD (Author)