The irreversible switch of one differentiated cell type to another is known as transdifferentiation. To consider that such cell‐type switching events arise through mistakes in normal development and tissue repair is a misnomer. It has long been accepted that many invertebrate organisms have the potential for transdifferentiation as part of their normal development or as a mechanism for replacing and regenerating lost or damaged tissue. Although their capacity for transdifferentiation is limited, this is also true for vertebrates and as such, several examples of naturally occurring, experimentally induced and disease‐related cell‐type interconversions have been described for higher organisms. These cell‐type conversions have important implications for understanding normal cell and tissue differentiation, the molecular and cellular basis of disease and may even facilitate the development of novel strategies for cell replacement and gene therapy in regenerative medicine.

Key Concepts

  • For a cell‐type conversion to be classified as transdifferentiation, two criteria have to be fulfilled (1) describe the loss of one cell phenotype and the gain of another and (2) demonstrate a direct ancestor–descendant relationship between the two cell types.
  • Transdifferentiation is associated with a discrete change in the programme of gene expression.
  • Transdifferentiation belongs to a broader group of cell type conversions called metaplasias.
  • Metaplasia is derived from the Greek word ‘metaplassein’ meaning ‘to mould into a new form’ and was first used to define the unexpected appearance of foreign tissues in ectopic sites.
  • Metaplasias also includes the conversion of one tissue‐specific stem cell to another tissue stem cell.
  • Some invertebrates demonstrate a remarkable capacity for transdifferentiation as part of their regenerative response to cell or tissue damage.
  • The potential for transdifferentiation in vertebrates is relatively limited compared to invertebrate organisms.
  • During transdifferentiation, cells pass through an intermediate state that may be progenitor‐like or unspecific, the nature of these intermediates is poorly understood.

Keywords: reprogramming; lens; liver; pancreas; oesophagus; differentiation; master regulator; gene expression

Figure 1. Life cycles of Turritopsis nutricula and C. elegans. (a) The life cycle of the hydrozoan Turritopsis nutricula begins with the production of gametes and progresses through Planula larvae, polyp, ephyrae and adult stages. When injured or faced with environmental stress adult Turritopsis nutricula undergo ontogeny reversal (green dashed arrow) whereby terminally differentiated cells undergo de‐differentiation to form a cyst‐like ball of cells that resembles the planular larvae stage. The cells in the cyst then re‐differentiate to form hydroid polyps that will progress through the normal stages of the life cycle eventually giving rise to sexually mature adult jellyfish. (b) The life cycle of the nematode C. elegans proceeds through an embryonic stage and four larval stages during which the animal gets progressively larger before reaching adulthood. During development, the rectum is lined by three pairs of epithelial cells designated K and K', U and F, and Y and B. In the second larval stage (L2) epithelial cell Y (orange) leaves the rectum and moves anteriorly. Cell Y transdifferentiates to become a motor neuron named PDA (red). By the fourth larval stage (L4), the newly transdifferentiated neuron PDA possesses an axon (red dashed line) that extends ventrally past the rectum before making a right‐handed commissure and projecting towards the anterior of the worm along the dorsal cord. takes place of Y.
Figure 2. Lens regeneration in amphibians. (a) Formation of the lens during eye development begins when the optic vesicle induces the overlying epidermis to become the optic placode (1). The optic placode invaginates towards the optic vesicle to form the lens vesicle (2). The lens placode then pinches off from the overlying epidermis to form a hollow lens vesicle, while the optic vesicle forms the eyecup (3). Cells on the anterior side of the lens vesicle proliferate and migrate into the centre of the lens (4). Lens cells start to manufacture crystallin proteins, lose their internal organelles and elongate to form transparent lens fibres (5). (b) Following experimental removal of the lens (1) pigmented epithelial cells of the dorsal iris begin to dedifferentiate and re‐enter the cell cycle (2). The dedifferentiating cells proliferate to form a structure that resembles the lens vesicle seen during normal development (3). Thereafter, the dedifferentiated pigmented epithelial cells re‐differentiate initiating a lens programme of gene expression. They produce crystallin proteins, elongate and form transparent lens fibres in a mechanism similar to that seen in development (4 and 5).
Figure 3. Lineage tracing during transdifferentiation of AR42J‐B13 cells to hepatocyte‐like cells. The AR42J‐B13 cell line was transiently transfected with a plasmid expressing nuclear‐GFP under the control of the elastase promoter. Cells in which the elastase promoter is active (acinar cells) exhibit nuclear GFP staining. Upon treatment with dexamethasone a proportion of the transdifferentiated hepatocytes also exhibit nuclear GFP indicating that they derived from acinar‐type cells within the original population.
Figure 4. Hepatocytes in the peri‐central region of the liver lobule transdifferentiate in the presence of Pdx‐1. In normal liver hepatocytes in the perivenous region of the liver lobule, immediately around the central vein, exhibit active Wnt signalling and express the ammonia metabolising enzyme glutamine synthase (GS). The remaining hepatocytes in the lobule have an inactive Wnt signalling pathway and they express the urea cycle enzyme carbamoyl phosphate synthetase (CPS). Upon infection with an adenovirus expressing the pancreatic transcription factor Pdx‐1 the cells in the perivenous region transdifferentiate to insulin‐producing β‐cells. The remaining cells in the lobule do not transdifferentiate despite expressing Pdx‐1. BD, bile duct; HA, hepatic artery and PV, portal vein.
Figure 5. The different regions of the gut tube are characterised by a specialised epithelium. (a) The oesophagus is lined by a stratified squamous epithelium consisting of cornified, granulated, spinous and basal cell layers. A single layer of columnar epithelium lines both the stomach and the intestine. In the stomach, it is organised into pits and glands. While in the intestine the epithelium is arranged into a series of crypts and villi. During development of the gut tube each region is characterised by the expression of specific transcription factors p63 and Sox 2 in the oesophagus, Sox 2 and Pdx1 in the stomach and Pdx 1 (duodenum only) Cdx 1 and Cdx 2 in the intestine. (b) Barrett's metaplasia is characterised by the ectopic appearance of intestinal‐type columnar epithelium in the stratified squamous epithelium lining the oesophagus. Intestinalisation of regions of the oesophagus is observed with robust expression of Cdx2 and the presence of goblet cells.


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Further Reading

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Zhang Z, Hu Y, Xu N, et al. (2019) A new way for beta cell neogenesis: transdifferentiation from alpha cells induced by glucagon‐like peptide 1. Journal of Diabetes Research 2019 (2583047): 1–11.

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Burke, Zoë, and Tosh, David(Dec 2019) Transdifferentiation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026053]