Transdifferentiation

Abstract

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. P12.pa 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.
close

References

Ber I, Shternhall K, Perl S, et al. (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. Journal of Biological Chemistry 278 (34): 31950–31957.

Berneman‐Zeitouni D, Molakandov K, Elgart M, et al. (2014) The temporal and hierarchical control of transcription factors‐induced liver to pancreas transdifferentiation. PLoS One 9 (2): e87812.

Brockenbrough JS, Weir GC and Bonner‐Weir S (1988) Discordance of exocrine and endocrine growth after 90% pancreatectomy in rats. Diabetes 37 (2): 232–236.

Brockes JP and Kumar A (2002) Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nature Reviews Molecular Cell Biology 3 (8): 566–574.

Carla EC, Pagliara P, Piraino S, Boero F and Dini L (2003) Morphological and ultrastructural analysis of Turritopsis nutricula during life cycle reversal. Tissue and Cell 35 (3): 213–222.

Chen X, Qin R, Liu B, et al. (2008) Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterology 8: 1.

Cohen H, Barash H, Meivar‐Levy I, et al. (2018) The Wnt/β‐catenin pathway determines the predisposition and efficiency of liver‐to‐pancreas reprogramming. Hepatology 68 (4): 1589–1603.

Colleypriest BJ, Burke ZD, Griffiths LP, et al. (2017) Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium. Differentiation 93: 39–49.

Del Rio‐Tsonis K, Washabaugh CH and Tsonis PA (1995) Expression of pax‐6 during urodele eye development and lens regeneration. Proceedings of the National Academy of Sciences of the United States of America 92 (11): 5092–5096.

Eguchi G and Shingai R (1971) Cellular analysis on localization of lens forming potency in the newt iris epithelium. Development, Growth and Differentiation 13 (4): 337–349.

Eguchi G, Abe SI and Watanabe K (1974) Differentiation of lens‐like structures from newt iris epithelial cells in vitro. Proceedings of the National Academy of Sciences of the United States of America 71 (12): 5052–5056.

Eguchi G and Kodama R (1993) Transdifferentiation. Current Opinion in Cell Biology 5 (6): 1023–1028.

Ferber S, Halkin A, Cohen H, et al. (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin‐induced hyperglycemia. Nature Medicine 6 (5): 568–572.

Guney MA and Gannon M (2009) Pancreas cell fate. Birth Defects Research Part C: Embryo Today: Reviews 87 (3): 232–248.

Hall M, Wenner J, Scherman P and Öberg S (2018) Intestinal metaplasia at the gastroesophageal junction is associated with gastroesophageal reflux but not with Helicobacter pylori infection. Scandinavian Journal of Gastroenterology 53 (10–11): 1179–1185.

Hameeteman W, Tytgat GN, Houthoff HJ and van den Tweel JG (1989) Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 96 (5 Pt 1): 1249–1256.

Hamilton SR and Yardley JH (1977) Regnerative of cardiac type mucosa and acquisition of Barrett mucosa after esophagogastrostomy. Gastroenterology 72 (4 Pt 1): 669–675.

Haveri H, Westerholm‐Ormio M, Lindfors K, et al. (2008) Transcription factors GATA‐4 and GATA‐6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterology 8: 9.

Hayashi K, Takahashi T, Kakita A and Yamashina S (1999) Regional differences in the cellular proliferation activity of the regenerating rat pancreas after partial pancreatectomy. Archives of Histology and Cytology 62 (4): 337–346.

Jarriault S, Schwab Y and Greenwald I (2008) A Caenorhabditis elegans model for epithelial‐neuronal transdifferentiation. Proceedings of the National Academy of Sciences of the United States of America 105 (10): 3790–3795.

Kazumori H, Ishihara S, Takahashi Y, Amano Y and Kinoshita Y (2011) Roles of Kruppel‐like factor 4 in oesophageal epithelial cells in Barrett's epithelium development. Gut 60 (5): 608–617.

Kong J, Nakagawa H, Isariyawongse BK, et al. (2009) Induction of intestinalization in human esophageal keratinocytes is a multistep process. Carcinogenesis 30 (1): 122–130.

Kragl M, Knapp D, Nacu E, et al. (2009) Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460 (7251): 60–65.

Lee BC, Hendricks JD and Bailey GS (1989) Metaplastic pancreatic cells in liver tumors induced by diethylnitrosamine. Experimental and Molecular Pathology 50 (1): 104–113.

Li Y, Wo JM, Ellis S, et al. (2006) Morphological transformation in esophageal submucosa by bone marrow cells: esophageal implantation under external esophageal perfusion. Stem Cells and Development 15 (5): 697–705.

Longnecker DS, Lilja HS, French J, Kuhlmann E and Noll W (1979) Transplantation of azaserine‐induced carcinomas of pancreas in rats. Cancer Letters 7 (4): 197–202.

Madhavan M, Haynes TL, Frisch NC, et al. (2006) The role of Pax‐6 in lens regeneration. Proceedings of the National Academy of Sciences of the United States of America 103 (40): 14848–14853.

Maki N, Takechi K, Sano S, et al. (2007) Rapid accumulation of nucleostemin in nucleolus during newt regeneration. Developmental Dynamics 236 (4): 941–950.

Maki N, Suetsugu‐Maki R, Tarui H, et al. (2009) Expression of stem cell pluripotency factors during regeneration in newts. Developmental Dynamics 238 (6): 1613–1616.

Michalopoulos GK and DeFrances MC (1997) Liver regeneration. Science 276 (5309): 60–66.

Michalopoulos GK (2007) Liver regeneration. Journal of Cellular Physiology 213 (2): 286–300.

Oliver G, Sosa‐Pineda B, Geisendorf S, et al. (1993) Prox 1, a prospero‐related homeobox gene expressed during mouse development. Mechanisms of Development 44 (1): 3–16.

Oliver G, Loosli F, Köster R, Wittbrodt J and Gruss P (1996) Ectopic lens induction in fish in response to the murine homeobox gene Six3. Mechanisms of Development 60 (2): 233–239.

Piessen G, Jonckheere N, Vincent A, et al. (2007) Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. Biochemical Journal 402 (1): 81–91.

Piraino S, Boero F, Aeschbach B and Schmid AV (1996) Reversing the life cycle: medusae transforming into polyps and cell transdifferentiation in Turritopsis nutricula (Cnidaria, Hydrozoa). Biological Bulletin 190 (3): 302–312.

Rao MS, Bendayan M, Kimbrough RD and Reddy JK (1986) Characterization of pancreatic‐type tissue in the liver of rat induced by polychlorinated biphenyls. Journal of Histochemistry and Cytochemistry 34 (2): 197–201.

Rao MS, Dwivedi RS, Subbarao V, et al. (1988) Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochemical and Biophysical Research Communications 156 (1): 131–136.

Selman K and Kafatos FC (1974) Transdifferentiation in the labial gland of silk moths: is DNA required for cellular metamorphosis? Cell Differentiation 3 (2): 81–94.

Shen CN, Slack JM and Tosh D (2000) Molecular basis of transdifferentiation of pancreas to liver. Nature Cell Biology 2 (12): 879–887.

Sousounis K, Qi F, Yadav MC, et al. (2015) A robust transcriptional program in newts undergoing multiple events of lens regeneration throughout their lifespan. eLife 4 1–17.

Suh E and Traber PG (1996) An intestine‐specific homeobox gene regulates proliferation and differentiation. Molecular and Cellular Biology 16 (2): 619–625.

Terada T and Nakanuma Y (1995) Expression of pancreatic enzymes (alpha‐amylase, trypsinogen, and lipase) during human liver development and maturation. Gastroenterology 108 (4): 1236–1245.

Tsonis PA, Trombley MT, Rowland T, Chandraratna RA and del Rio‐Tsonis K (2000) Role of retinoic acid in lens regeneration. Developmental Dynamics 219 (4): 588–593.

Tsonis PA, Vergara MN, Spence JR et al. (2004) A novel role of the hedgehog pathway in lens regeneration. Developmental Biology 267 (2): 450–461.

Wang DH, Clemons NJ, Miyashita T, et al. (2010) Aberrant epithelial–mesenchymal Hedgehog signaling characterizes Barrett's metaplasia. Gastroenterology 138 (5): 1810–1822.

Wang X, Ouyang H, Yamamoto Y, et al. (2011) Residual embryonic cells as precursors of a Barrett's‐like metaplasia. Cell 145 (7): 1023–1035.

Westmacott A, Burke ZD, Oliver G, Slack JM and Tosh D (2006) C/EBPalpha and C/EBPbeta are markers of early liver development. International Journal of Developmental Biology 50 (7): 653–657.

Wolf HK, Burchette JL Jr, Garcia JA and Michalopoulos G (1990) Exocrine pancreatic tissue in human liver: a metaplastic process? American Journal of Surgical Pathology 14 (6): 590–595.

Wolfe‐Coote S, Louw J, Woodroof C and Du Toit DF (1996) The non‐human primate endocrine pancreas: development, regeneration potential and metaplasia. Cell Biology International 20 (2): 95–101.

Yang Y and Zalik SE (1994) The cells of the dorsal iris involved in lens regeneration are myoepithelial cells whose cytoskeleton changes during cell type conversion. Anatomy and Embryology 189 (6): 475–487.

Zuryn S, Ahier A, Portoso M, et al. (2014) Transdifferentiation. Sequential histone‐modifying activities determine the robustness of transdifferentiation. Science 345 (6198): 826–829.

Further Reading

Banga A, Akinci E, Greder LV, Dutton JR and Slack JMW (2012) In vivo reprogramming of Sox9+ cells in the liver to insulin‐secreting ducts. Proceedings of the National Academy of Sciences of the United States of America 109 (38): 15336–15341.

Grogg MW, Call MK, Okamoto M, et al. (2005) BMP inhibition‐driven regulation of six‐3 underlies induction of newt lens regeneration. Nature 438 (7069): 858–862.

Luo L, Hu DH, Yin JQ and Xu R‐X (2018) Molecular mechanisms of transdifferentiation of adipose‐derived stem cells into neural cells: current status and perspectives. Stem Cells International 2018 (5630802): 1–14.

O'Neill KE, Thowfeequ S, Li W‐C, et al. (2014) Hepatocyte‐ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα. Cellular Reprogramming 16 (5): 314–323.

Riddle MR, Spickard EA, Jevince A, et al. (2016) Transorganogenesis and transdifferentiation in C. elegans are dependent on differentiated cell identity. Developmental Biology 420 (1): 136–147.

Sumazaki R, Shiojiri N, Isoyama S, et al. (2004) Conversion of biliary system to pancreatic tissue in Hes1‐deficient mice. Nature Genetics 36 (1): 83–87.

Ye L, Robertson MA, Hesselson D, Stainier DYR and Anderson RM (2015) Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis. Development 142 (8): 1407–1417.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Burke, Zoë, and Tosh, David(Dec 2019) Transdifferentiation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026053]