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Plasticity and reprogramming of differentiated cells in amphibian regeneration

Nature Reviews Molecular Cell Biology volume 3, pages 566–574 (2002)Cite this article

Key Points

  • Regenerative ability is widespread in metazoan phylogeny, but has been lost in many species for reasons that are not understood.

  • The champions of regeneration among adult verterbrates are the urodele amphibians, such as the newt, which can regenerate their limbs, jaws, lens and large sections of the heart.

  • Urodele regeneration depends on the local plasticity of differentiated cells that remain after injury or tissue removal. This involves re-entry to the cell cycle and loss of differentiated characteristics, so as to generate a local progenitor cell of restricted potentiality.

  • The molecular cell biology of urodele plasticity has been investigated in detail in the skeletal myofibre and myotube. Newt myotubes can re-enter the cell cycle by activating a pathway that leads to phosphorylation of the retinoblastoma protein pRb. This pathway is triggered by a ligand that is generated downstream of thrombin activation to which mammalian myotubes are completely unresponsive.

  • Newt myotubes are converted to mononucleate progeny after implantation into the regenerating limb. Mouse myotubes are also converted to mononucleate cells by expression of the Msx-1 gene, by exposure to a substituted purine known as myoseverin or to extracts of a regenerating newt limb.

  • Our understanding of re-programming during urodele regeneration might lead to a marked enhancement of regenerative ability in mammals.

Abstract

Adult urodele amphibians, such as the newt, can regenerate their limbs and various other structures. This is the result of the plasticity and reprogramming of residual differentiated cells, rather than the existence of a 'reserve-cell' mechanism. The recent demonstrations of plasticity in mouse myotubes should facilitate comparative studies of the pathways that underlie the regenerative response, as well as proposing new approaches to promote mammalian regeneration.

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Figure 1: Urodele limb regeneration.
Figure 2: Plasticity of differentiated cells during regeneration of newt heart or lens.
Figure 3: Plasticity of urodele myogenesis.
Figure 4: Thrombin activity counteracts post-mitotic arrest in newt myotubes.
Figure 5: Arrested myotubes undergo cellularization after implantation into the newt blastema.
Figure 6: Categories of genes that are regulated after myoseverin treatment of myotubes or serum stimulation of fibroblasts.

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Author information

Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK

    Jeremy P. Brockes & Anoop Kumar

Authors
  1. Jeremy P. Brockes
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  2. Anoop Kumar
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Corresponding author

Correspondence to Jeremy P. Brockes.

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DATABASES

LocusLink

CDK4

EGF

Msx-1

pRb

prothrombin

Swiss-Prot

GFP

p16INK4

FURTHER READING

Encyclopedia of Life Sciences

Regeneration: growth factors in limb development

Regeneration of the urodele limb

Regeneration of the vertebrate lens and other eye structures

Regeneration of the vertebrate tail

Regeneration of vertebrate appendages

Regeneration of vertebrate tissues: model systems

Regeneration: principles

Spallanzani

Glossary

URODELE

An order of the class Amphibia, which comprises newts and salamanders, which have elongated bodies, short limbs and a tail.

METAZOAN

Refers to the kingdom Animalia (animals), which comprises ∼35 phyla of multicellular organisms.

PHYLOGENY

Evolutionary history that is sometimes represented by the hypothesized ancestor–descendant relationship of a group of organisms.

CARDIOMYOCYTE

A muscle cell of the heart.

S (SYNTHESIS) PHASE

The phase of the eukaryotic cell cycle in which DNA is synthesized.

MYOFIBRIL

The structural unit of striated muscle fibres. Several myofibrils make up each fibre.

MYOTUBE

The multinucleate structure that is formed by the fusion of proliferating myoblasts and is characterized by the presence of certain muscle-specific marker proteins.

MYOFIBRE

A skeletal-muscle fibre that consists of one long multinucleate cell.

PLURIPOTENT CELL

A stem cell that can give rise to more than one differentiated cell type.

HEPATOCYTES

The parenchymal cells of the liver that are responsible for the synthesis, degradation and storage of a wide range of substances.

ROTIFERA

A small phylum of microscopic multicellular organisms. They have a wheel-like ciliated organ (from which they derive their name) that they use for swimming and feeding.

TURBELLARIANS

A class of platyhelminthes that comprises mostly aquatic and free-living organisms. They have a ciliated epidermis for locomotion and a simple gut.

ANNELID

A segmented worm.

PLANARIAN

Describes free-living members of the invertebrate phylum platyhelminthes.

SCHWANN CELL

A cell that produces myelin and ensheathes axons in the peripheral nervous system.

MYELIN

Proteins that are produced by Schwann cells or oligodendrocytes that cause adjacent plasma membranes to stack tightly together.

MESENCHYME

Immature connective tissue that consists of cells that are embedded in extracellular matrix.

GREEN FLUORESCENT PROTEIN

An autofluorescent protein that was originally isolated from the jellyfish Aequorea victoria. It can be genetically conjugated with proteins to make them fluorescent. The most widely used mutant, EGFP, has an emission maximum at 510 nm.

5′ BROMODEOXYURIDINE

(BrdU). A base analogue of thymidine, which is often used experimentally to label dividing cells.

NOMARSKI OPTICS

Also known as differential interference contrast microscopy, this technique forms images of high contrast and resolution in unstained cells using birefringent prisms and polarized light.

EXOCRINE CELL

A cell that makes up part of an exocrine gland, which discharges its secretion through a duct.

G2

The phase of the cell cycle through which cells progress after S phase but before M phase.

HETEROKARYON

A cell that contains two nuclei in a common cytoplasm.

CYTOKINESIS

The process of cytoplasmic division.

OSTEOCLAST

A mesenchymal cell that can differentiate into a bone-degrading cell.

GIANT CELLS

Large multinucleated cells that are thought to result from the fusion of macrophages.

CHONDROGENIC

Able to form cartilage.

ADIPOGENIC

Able to form fat or adipose tissue.

MICROTUBULE

A hollow tube, 25 nm in diameter, that is formed by the lateral association of 13 protofilaments, which are themselves polymers of α- and β-tubulin subunits.

DNA MICROARRAYS

Devices that are used to analyse complex nucleic acid samples by hybridization. They make it possible to quantitate the amount of different nucleic acid molecules that are present in a sample of interest.

CRYOGENIC INFARCTION

Obstruction of the blood supply as a result of extremely low temperatures.

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Brockes, J., Kumar, A. Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nat Rev Mol Cell Biol 3, 566–574 (2002). https://doi.org/10.1038/nrm881

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