Cell and Tissue RegenerationDr IMRANA

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.

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).

The ability of tissues to repair themselves is determined, in part, by their intrinsicproliferative capacity.Tissues of the body are divided into three groups.Labile (continuously dividing) tissuesStable tissuesPermanent tissues

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.

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

Stable tissuesCells of these tissues are quiescent (in the G0 stage of the cell cycle) and have only minimal proliferative activity in their normal stateThese 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.

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

Permanent tissuesThe 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 occurin some areas of the adult brain, and there is some evidencethat heart muscle cells may proliferate after myocardialnecrosis. Nevertheless, whatever proliferative capacity may exist in these tissues, it is insufficient to produce tissue regeneration after injury.

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.

Cell proliferation is driven by signalsProvided 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 macrophagesepithelial and stromal cells also produce some of these factors.

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)

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 cellsfor regeneration after injury are tissue stem cells(stem cells live in specialized niches)

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

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.

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.

The mechanisms underlying this responseare 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.

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.

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.

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.

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.

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

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.

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

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.

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.

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.

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.

Termination, phase Hepatocytes return to quiescence.

Antiproliferative cytokines of the TGF-β family are likely involved.

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.

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.

References

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