Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

How cells change their phenotype

Nature Reviews Molecular Cell Biology volume 3, pages 187–194 (2002)Cite this article

Key Points

  • The terms 'metaplasia' and 'transdifferentiation' are defined. Metaplasia is the conversion of one cell or tissue type into another and transdifferentiation (a subset of metaplasia) is the conversion of one differentiated cell type to another, with or without an intervening cell division. Methods for proving their occurrence are described.

  • Examples are presented of bone-marrow-derived stem cells that give rise to cells of completely different embryonic lineages following transplantation.

  • Purified haematopoietic stem cells have been shown to convert to liver cells or to cells of the central nervous system.

  • Well-characterized examples of transdifferentiation include conversion of pancreas to liver, myoblasts to adipocytes and iris to lens.

  • Metaplasias arise by switching of the state of key developmental control genes, some of which have been identified.

  • It remains unclear whether the marked cell-type changes of grafted bone-marrow cells reflect a role for these cells in normal renewal of all tissues, or whether it is a rare phenomenon at the cellular level that is associated with the irradiation of the hosts.

Abstract

Recent attention has focused on the remarkable ability of adult stem cells to produce differentiated cells from embryologically unrelated tissues. This phenomenon is an example of metaplasia and shows that embryological commitments can be reversed or erased under certain circumstances. In some cases, even fully differentiated cells can change their phenotype (transdifferentiation). This review examines recently discovered cases of metaplasia, and speculates on the potential molecular and cellular mechanisms that underlie the switches, and their significance to developmental biology and medicine.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stem cells can undergo self-renewal and generate transit cells and, finally, differentiated cells.
Figure 2: Transdifferentiation of hepatocytes from pancreatic exocrine cells.
Figure 3: A theoretical model for the occurrence of transdifferentiation.
Figure 4: The Cre/lox system can be used for lineage analysis.

Similar content being viewed by others

References

  1. Slack, J. M. W. & Tosh, D. Transdifferentiation and metaplasia—switching cell types. Curr. Opin. Genet. Dev. 11, 581–586 (2001).

    Article  CAS  Google Scholar 

  2. Lawrence, P. A. & Morata, G. The elements of the bithorax complex. Cell 35, 595–601 (1983).

    Article  CAS  Google Scholar 

  3. Wakimoto, B. T. & Kaufman, T. C. Analysis of larval segmentation in lethal genotypes associated with the antennapedia gene complex in Drosophila melanogaster. Dev. Biol. 81, 51–64 (1981).

    Article  CAS  Google Scholar 

  4. Hadorn, E. Problems of determination and transdetermination. Brookhaven Symp. Biol. 18, 148–161 (1965).

    Google Scholar 

  5. Eguchi, G. & Kodama, R. Transdifferentiation. Curr. Opin. Cell Biol. 5, 1023–1028 (1993).

    Article  CAS  Google Scholar 

  6. Brockes, J. P., Kumar, A. & Velloso, C. P. Regeneration as an evolutionary variable. J. Anat. 199, 3–11 (2001).

    Article  CAS  Google Scholar 

  7. Zambrowicz, B. P. et al. Disruption of overlapping transcripts in the ROSAβ–geo26 gene trap strain leads to widespread expression of β-galactosidase in mouse embryos and haematopoietic cells. Proc. Natl Acad. Sci. USA 94, 3789–3794 (1997).

    Article  CAS  Google Scholar 

  8. Reyes, M. et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98, 2615–2625 (2001).

    Article  CAS  Google Scholar 

  9. Priller, J. et al. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J. Cell Biol. 155, 733–738 (2001).The authors found that transplanted bone marrow cells were able to generate highly differentiated neurons.

    Article  CAS  Google Scholar 

  10. Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nature Med. 7, 1356–1361 (2001).

    Article  CAS  Google Scholar 

  11. Alison, M. R. et al. Hepatocytes from non-hepatic adult stem cells. Nature 406, 257 (2000).

    Article  CAS  Google Scholar 

  12. Theise, N. D. et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31, 235–240 (2000).

    Article  CAS  Google Scholar 

  13. Herrera, P. L. Adult insulin and glucagon producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000).

    CAS  Google Scholar 

  14. Beresford, W. A. Direct transdifferentiation: can cells change their phenotype without dividing? Cell Differ. Dev. 29, 81–93 (1990).

    Article  CAS  Google Scholar 

  15. Slack, J. M. W. Essential Developmental Biology (Blackwell Science, Oxford, 2001)

    Google Scholar 

  16. Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287, 1442–1446 (2000).

    Article  CAS  Google Scholar 

  17. Watt, F. M. & Hogan, B. L. M. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).

    Article  CAS  Google Scholar 

  18. Toma, J. G et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature Cell Biol. 3, 778–784 (2001).Following the isolation of a new type of skin stem cell, the authors show that these cells can be converted to various differentiated cell types in vitro including neurons and glia, smooth muscle cells and adipocytes.

    Article  CAS  Google Scholar 

  19. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    Article  CAS  Google Scholar 

  20. Alison, M. R. & Sarraf, C. Hepatic stem cells. J. Hepatol. 29, 676–682 (1998).

    Article  CAS  Google Scholar 

  21. Suzuki, A. et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J. Cell Biol. 156, 173–184 (2002).Report of the isolation of hepatic stem cells. When the cells were transplanted into recipients they differentiated into hepatocytes and bile-duct cells. These cells also have the potential to differentiate in vivo into acinar and ductal pancreatic cells and intestinal epithelial cells.

    Article  CAS  Google Scholar 

  22. Whitehead, R. H., Demmler, K., Rockman, S. P. & Watson, N. K. Clonogenic growth of epithelial cells from normal colonic mucosa from both mice and humans. Gastroenterology 117, 858–865 (1999).

    Article  CAS  Google Scholar 

  23. Seale, P. & Rudnicki, M. A. A new look at the origin, function, and 'stem-cell' status of muscle satellite cells. Dev. Biol. 218, 115–124 (2000).

    Article  CAS  Google Scholar 

  24. Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).

    Article  CAS  Google Scholar 

  25. Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science, 279, 1528–1530 (1998).Demonstration of the formation of muscle from transplanted bone marrow taken from a transgenic mouse line in which a muscle promoter (the myosin light chain 3F promoter) was used to drive nuclear β-galactosidase.

    Article  CAS  Google Scholar 

  26. Petersen, B. E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).

    Article  CAS  Google Scholar 

  27. Theise, N. D. et al. Liver from bone marrow in humans. Hepatology 32, 11–16 (2000).

    Article  CAS  Google Scholar 

  28. Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000).The authors isolated a highly purified population of haematopoietic stem cells derived from bone marrow and showed that they could be used as a source of hepatocytes.

    Article  CAS  Google Scholar 

  29. Grompe, M. et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nature Genet. 10, 453–460 (1995).

    Article  CAS  Google Scholar 

  30. Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).

    Article  CAS  Google Scholar 

  31. Poulsom, R. et al. Bone marrow contributes to renal parenchymal turnover and regeneration. J. Pathol. 195, 229–235 (2001).

    Article  CAS  Google Scholar 

  32. Eglitis, M. A. & Mezey, F. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc. Natl Acad. Sci. USA 94, 4080–4085 (1997).

    Article  CAS  Google Scholar 

  33. Kondo, T. & Raff, M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289, 1754–1757 (2000).

    Article  CAS  Google Scholar 

  34. Jackson, K. A., Mi, T. & Goodell, M. A. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc. Natl Acad. Sci. USA 96, 14482–14486 (1999).

    Article  CAS  Google Scholar 

  35. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).

    CAS  Google Scholar 

  36. Pang, W. Role of muscle-derived cells in hematopoietic reconstitution of irradiated mice. Blood 95, 1106–1108 (2000).

    CAS  Google Scholar 

  37. Rao, M. S. et al. Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochem. Biophys. Res. Commun. 156, 131–136 (1988).

    Article  CAS  Google Scholar 

  38. Rao, M. S. et al. Role of periductular and ductular epithelial cells of the adult rat pancreas in pancreatic hepatocyte lineage. Am. J. Pathol. 134, 1069–1086 (1989).

    CAS  Google Scholar 

  39. Rao, M. S., Yeldandi, A. V. & Reddy, J. K. Stem cell potential of ductular and periductular cells in the adult rat pancreas. Cell Differ. Dev. 29, 155–163 (1990).

    Article  CAS  Google Scholar 

  40. Reddy, J. K. et al. Pancreatic hepatocytes, an in vivo model for cell lineage in pancreas of adult rat. Dig. Dis. Sci. 4, 502–509 (1991).

    Article  Google Scholar 

  41. Dabeva, M. D. et al. Differentiation of pancreatic epithelial progenitor cells into hepatocytes. Proc. Natl Acad. Sci. USA 94, 7356–7361 (1997).

    Article  CAS  Google Scholar 

  42. Krakowski, M. L. et al. Pancreatic expression of keratinocyte growth factor leads to differentiation of islet hepatocytes and proliferation of duct cells. Am. J. Pathol. 154, 683–691 (1999).

    Article  CAS  Google Scholar 

  43. Rao, M. S., Bendayan, M., Kimbrough, R. D. & Reddy, J. K. Characterization of pancreatic-type tissue in the liver of rat induced by polychlorinated biphenyls. J. Histochem. Cytochem. 34, 197–201 (1986).

    Article  CAS  Google Scholar 

  44. Shen, C. N., Slack, J. M. W. & Tosh, D. Molecular basis of transdifferentiation of pancreas to liver. Nature Cell Biol. 2, 879–887 (2000).

    Article  CAS  Google Scholar 

  45. Reddy, J. K. et al. Induction and origin of hepatocytes in rat pancreas. J. Cell Biol. 98, 2082–2090 (1984).

    Article  CAS  Google Scholar 

  46. Bossard, P., McPherson, C. E. & Zaret, K. S. Methods: A Companion to Methods in Enzymology 11, 180–188 (1997).

  47. Hu, E., Tontonoz, P. & Spiegelman, B. M. Transdifferentiation of myoblasts by the adipogenic transcription factors PPARγ and C/EBPα. Proc. Natl Acad. Sci. USA 92, 9856–9860 (1995).

    Article  CAS  Google Scholar 

  48. Ross, S. E. et al. Inhibition of adipogenesis by Wnt signaling. Science 289, 950–953 (2000).

    Article  CAS  Google Scholar 

  49. Kosaka, M., Kodama, R. & Eguchi, G. In vitro culture system for iris-pigmented epithelial cells for molecular analysis of transdifferentiation. Exp. Cell Res. 245, 245–251 (1998).

    Article  CAS  Google Scholar 

  50. Ashery-Padan, R. & Gruss, P. Pax6 lights-up the way for eye development. Curr. Opin. Cell Biol. 13, 706–714 (2001).

    Article  CAS  Google Scholar 

  51. Oliver, G., Loosli, F., Koster, R., Wittbrodt, J. & Gruss, P. Ectopic lens induction in fish in response to the murine homeobox gene Six3. Mech. Dev. 60, 233–239 (1996).

    Article  CAS  Google Scholar 

  52. Altmann, C. R., Chow, R. L., Lang, R. A. & Hemmati-Brivanlou, A. Lens induction by Pax-6 in Xenopus laevis. Dev. Biol. 185, 119–123 (1997).

    Article  CAS  Google Scholar 

  53. Beck, F., Chawengsaksophak, K., Waring, P., Playford, R. J. & Furness, J. B. Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice. Proc. Natl Acad. Sci. USA 96, 7318–7323 (1999).

    Article  CAS  Google Scholar 

  54. Weintraub, H. et al. Activation of muscle-specific genes in pigment, nerve, fat, liver and fibroblast cell lines by forced expression of MyoD. Proc. Natl Acad. Sci. USA 86, 5434–5438 (1989).

    Article  CAS  Google Scholar 

  55. Halder, G., Callaerts, P. & Gehring, W. J. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267, 1788–1792 (1995).

    Article  CAS  Google Scholar 

  56. Slack, J. M. W. Homeotic transformations in Man: implications for the mechanism of embryonic development and for the organization of epithelia. J. Theor. Biol. 114, 463–490 (1985).

    Article  CAS  Google Scholar 

  57. Slack, J. M. W. Epithelial metaplasia and the second anatomy. Lancet 2, 268–271 (1986).

    Article  CAS  Google Scholar 

  58. Slack, J. M. W. in Oxford Textbook of Pathology (eds McGee J. O'D., Isaacson, P. G. & Wright, N. A.) 565–568 (Oxford Univ. Press, Oxford, 1992).

    Google Scholar 

  59. Jankowski, J. A., Harrison, R. F., Perry, I., Balkwill, F. & Tselepis, C. Barrett's metaplasia. Lancet 356, 2079–2085 (2000).

    Article  CAS  Google Scholar 

  60. Jankowski, J. A. et al. Molecular evolution of the metaplasia–dysplasia–adenocarcinoma sequence in the esophagus. Am. J. Pathol. 154, 965–973 (1999).

    Article  CAS  Google Scholar 

  61. Bittner, R. E. et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat. Embryol. (Berl.) 199, 391–396 (1999).

    Article  CAS  Google Scholar 

  62. Shi, Q. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 92, 362–367 (1998).

    CAS  Google Scholar 

  63. Jackson, K. A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).

    Article  CAS  Google Scholar 

  64. Brazelton, T. R., Rossi, F. M. V., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000).

    Article  CAS  Google Scholar 

  65. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. & McKercher, S. R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1779–1782 (2000).

    Article  CAS  Google Scholar 

  66. Orlic, D. et al. Bone marrow cells regenerate infracted myocardium. Nature 410, 701–705 (2001).

    Article  CAS  Google Scholar 

  67. Bjornson, C. R. R., Rietze, R. L., Reynolds, B. A., Magli, M. C. & Vescovi, A. L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283, 534–537 (1999).

    Article  CAS  Google Scholar 

  68. Galli, R. et al. Skeletal myogenic potential of human and mouse neural stem cells Nature Neurosci. 3, 986–991 (2000).

    Article  CAS  Google Scholar 

  69. Clarke, D. L. et al. Generalized potential of adult neural stem cells. Science 288, 1660–1663 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We apologize to the many colleagues whose work is not discussed owing to space limitations. The research in the authors' labs is supported by the Medical Research Council and Wellcome Trust.

Author information

Authors and Affiliations

  1. Department of Biology and Biochemistry, Developmental Biology Programme, University of Bath, Bath, BA2 7AY, UK

    David Tosh & Jonathan M. W. Slack

Authors
  1. David Tosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan M. W. Slack
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Tosh.

Related links

Related links

DATABASES

LocusLink

albumin

glutamic acid decarboxylase

MRF4

transferrin

 OMIM

Barrett's metaplasia

squamous cell carcinoma

tyrosinaemia, type I

 Swiss-Prot

calbindin-D28K

Cdx2

C/EBPα

C/EBPβ

Cre

FAH

FGF-2

β-galactosidase

GFAP

GFP

Myf-5

MyoD

myogenin

Pax-6

PPAR-γ

sine oculis

Six-3

TCF4

transthyretin

Wnt-10b

FURTHER READING

Goodell lab (protocols for the isolation of bone marrow stem-cell purification and stem cells from murine muscle)

Grompe lab homepage

Metaplasia

Glossary

METAPLASIA

The conversion of one cell or tissue type into another. Includes transdifferentiation and also conversion between undifferentiated stem cells of different tissues.

STEM CELL

A cell that has the potential to divide and produce a replica cell as well as differentiated progeny.

DIFFERENTIATION

The synthesis of proteins that are produced selectively in a single cell type (for example, albumin in hepatocytes). Differentiation is generally reflected in specialized structure (such as bile canaliculi) and function (such as synthesis of bile).

EPIGENETIC CHANGE

A sTable change in phenotype that arises from processes other than the alteration of sequences of bases in genomic DNA.

DYSPLASIA

A cellular growth abnormality in which the cellular appearance is altered and tissue architecture might be disturbed.

HOMEOTIC MUTATIONS

A class of mutations in which a given tissue or body part develops in the same way as one that is normally present in another part of the body.

IMAGINAL DISCS

Single-cell layer epithelial structures of the Drosophila larva that give rise to wings, legs and other appendages.

DETERMINATION

The irreversible commitment of a cell to follow a pathway of development.

CRE/lox

A site-specific recombination system derived from Escherichia coli bacteriophage P1. Two short DNA sequences (lox sites) are engineered to flank the target DNA. Activation of the Cre-recombinase enzyme catalyses recombination between the lox sites, leading to excision of the intervening sequence.

5′ BROMODEOXYURIDINE

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

COMMITMENT

The intrinsic nature of a cell to follow a pathway of development.

CHONDROCYTE

A differentiated cell of cartilage tissue.

OSTEOBLAST

A mesenchymal cell with the capacity to differentiate into bone tissue.

HEREDITARY TYROSINAEMIA TYPE I

An autosomal recessive condition caused by mutation of the FAH gene. Patients have increased levels of tyrosine in the blood, and symptoms include deterioration of the liver and accumulation of other amino acids, such as methionine in the blood and urine.

PARENCHYMAL TISSUE

All tissue other than lymphoid tissue. Lymphoid tissue is derived from the bone marrow, whereas parenchymal tissue is not.

ASTROCYTE

A star-shaped glial cell that supports the tissue of the central nervous system.

OLIGODENDROCYTE

A glial cell in the nervous system that forms a myelin sheath around axons.

MICROGLIA

Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

ECTODERM

The outermost germ layer of the developing embryo. It gives rise to the epidermis and the nerves.

PURKINJE CELLS

Large, pear-shaped cells of the cerebellum, which are connected to multi-branched nerve cells that cross the cerebellar cortex.

ENDODERM

The innermost germ layer of the developing embryo. It gives rise to the epithelia of the lung, digestive tract, bladder and urethra.

PLURIPOTENCY

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

GLIAL CELLS

Non-neuronal cells of the central nervous system, which comprise astrocytes, oligodendrocytes, microglia and ependymal cells.

SPECIFICATION

A labile form of commitment, which can be altered by environmental signals.

MESODERM

The middle germ layer of the developing embryo. It gives rise to the musculoskeletal, vascular and urinogenital systems, and to connective tissue (including that of the dermis).

TROPHOBLAST

The surface cell layers of an embryo at the blastocyst stage.

HETEROTOPIAS

A misplaced tissue, which arises during embryogenesis.

INTERCALARY REGENERATION

Regeneration that occurs at a junction between experimentally joined body parts, which results in the re-formation of parts that normally lie between them.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tosh, D., Slack, J. How cells change their phenotype. Nat Rev Mol Cell Biol 3, 187–194 (2002). https://doi.org/10.1038/nrm761

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm761

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing