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Metaplasia and transdifferentiation: from pure biology to the clinic

Nature Reviews Molecular Cell Biology volume 8, pages 369–378 (2007)Cite this article

Key Points

  • 'Metaplasia' is defined as the conversion of one tissue type to another, whereas 'transdifferentiation' is defined as the conversion of one differentiated cell type to another. Despite scepticism arising from exaggerated claims about the reprogramming of bone-marrow stem cells, these phenomena do occur on occasion.

  • Long standing examples are the phenomena of transdetermination in Drosophila melanogaster and the types of epithelial metaplasia in which patches of one epithelium are found in the midst of another.

  • The cause of such events is the alteration of expression of the transcription factors that encode the specification of the tissue types during embryonic development. The alteration can arise from somatic mutation, epigenetic change or change of regulation by an extracellular signal. Metaplasias are associated with tissue damage because the process of regeneration gives small foci of ectopic tissue the opportunity to grow into large patches.

  • Many metaplasias are understood in molecular detail, and the following are described: transdetermination of leg to wing in D. melanogaster; intestinal metaplasia in human and mouse; vaginal adenosis in women; switching of B lymphocytes to macrophages; transformation of exocrine pancreas to hepatocytes; and Wolffian regeneration of the lens from the iris in newts.

  • The nature of the differentiated state, and that of the commitment of undifferentiated stem and progenitor cell populations remains poorly understood, although it is likely that chromatin structure is involved.

  • Therapeutic applications can be imagined in which the expression of relevant transcription factors is modified. These could potentially be used to inhibit the formation of harmful metaplasias, such as those that predispose individuals to cancer. They could also be used to generate desirable cell types, such as pancreatic β cells, for transplantation therapy.

Abstract

Transformations from one tissue type to another make up a well established set of phenomena that can be explained by the principles of developmental biology. Although these phenomena might be rare in nature, we can now imagine the possibility of deliberately reprogramming cells from one tissue type to another by manipulating the expression of transcription factors. This approach could generate new therapies for many human diseases.

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Figure 1: A simple developmental hierarchy.
Figure 2: Diagram of human embryo gut at ∼35 days gestation.
Figure 3: How homeotic mutations can alter the character of body parts.
Figure 4: Model for metaplasia.
Figure 5: Growth of a metaplastic focus by replacement of neighbouring structural-proliferative units.
Figure 6: Developmental memory.

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Acknowledgements

Research in the author's laboratory is supported by the Wellcome Trust, the Medical Research Council, EU Framework 6 and Sulis Innovation. I am grateful to D. Tosh, J. Dutton, D. Eberhard, K. O'Neill and R. Slack for comments on the manuscript.

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  1. Centre for Regenerative Medicine, University of Bath, BA27AY, Bath, UK

    Jonathan M. W. Slack

  2. Stem Cell Institute, University of Minnesota MTRF, 2001 6th Street SE, 2873, Minneapolis, 55455, Minnesota, USA

    Jonathan M. W. Slack

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Glossary

Differentiated cell

A differentiated cell is a functional cell of a particular type, usually identifiable by its specific appearance under the light microscope. Examples include a neuron, an intestinal absorptive cell and a cartilage cell.

Pluripotent

Able to become one of several types of differentiated cell.

Transdetermination

A term used in D. melanogaster genetics to indicate a change of commitment of imaginal disc cells such that they will become one disc type rather than another, for example wing instead of leg.

Haemolymph

The blood of an insect or other arthropod. Unlike the blood of vertebrates, the haemolymph normally fills the whole body cavity.

Serial heteromorphosis

'Heteromorphosis' means a body part or tissue that is developing in the wrong place during embryogenesis or regeneration. 'Serial', in this context, relates to a set of body parts formed by similar developmental mechanisms, such as the segments or appendages of an arthropod.

Endoderm

The endoderm is the innermost of the three germ layers of an early embryo. In vertebrates, the endoderm becomes the epithelial lining of the gut and the respiratory system.

Allantoic evagination

The allantois is an extra-embryonic structure of higher vertebrate embryos. In the human embryo, it consists of an outgrowth of the hindgut, which enters the umbilical cord.

Hox gene system

The Hox genes encode a set of transcription factors that are concerned with specifying the head-to-tail sequence of body parts during the embryonic development of animals.

Heterotopia

A body part or tissue that developed in the wrong place during the course of embryonic development.

Pancreatic exocrine cells

The cells of the pancreas that secrete digestive enzymes.

Undifferentiated cell

An undifferentiated cell is one that is not differentiated. Most undifferentiated cells are stem or progenitor cells. They can have a commitment to form a particular body part or tissue type.

Mesoderm

The mesoderm is the middle one of the three germ layers of an early embryo. In vertebrates, the mesoderm becomes the muscles, circulatory system, kidneys and connective tissues.

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Slack, J. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat Rev Mol Cell Biol 8, 369–378 (2007). https://doi.org/10.1038/nrm2146

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