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Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style

Key Points

  • Mature, terminally differentiated cells have the capacity to de-differentiate or transdifferentiate in vivo.

  • De-differentiation and transdifferentiation can be forced experimentally, but these processes also occur physiologically in response to tissue injury and/or cell loss.

  • Cellular plasticity involves the repression of genes associated with the previous cell type, as well as activation of genes associated with the new cell type.

  • Cells may occupy 'intermediate' identity states while undergoing de-differentiation or transdifferentiation. Such changes can be reversible.

  • Cellular plasticity can be driven by factors that induce a new identity or by the loss of inhibitory factors that maintain the old identity.

Abstract

Biologists have long been intrigued by the possibility that cells can change their identity, a phenomenon known as cellular plasticity. The discovery that terminally differentiated cells can be experimentally coaxed to become pluripotent has invigorated the field, and recent studies have demonstrated that changes in cell identity are not limited to the laboratory. Specifically, certain adult cells retain the capacity to de-differentiate or transdifferentiate under physiological conditions, as part of an organ's normal injury response. Recent studies have highlighted the extent to which cell plasticity contributes to tissue homeostasis, findings that have implications for cell-based therapy.

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Figure 1: Models of differentiation, de-differentiation and transdifferentiation.
Figure 2: Examples of de-differentiation.
Figure 3: Signalling from surrounding cells and the environment induces de-differentiation.
Figure 4: Transdifferentiation in the liver and pancreas leads to tissue repair.

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Acknowledgements

The authors are indebted to Pantelis Rompolas for helpful comments on the manuscript. A.M. is supported by a grant from the Cholangiocarcinoma Foundation. B.Z.S. is supported by grants from the US National Institutes of Health (NIH; DK104196 and CA169123), the Penn Institute for Regenerative Medicine, the Biesecker Pediatric Liver Center and the Abramson Family Cancer Research Institute.

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Glossary

Progenitor cell

An immature cell, often lineage-restricted, that can proliferate and give rise to differentiated cells. This is often a short-term state compared to stem cell populations, which may be maintained for a lifetime. Progenitor cells are also sometimes referred to as transit-amplifying cells.

Reprogramming

A change in the identity of a differentiated cell. Usage of this term often overlaps with de- and transdifferentiation, although reprogramming generally refers to a complete and stable shift. The most extreme example is reprogramming of a differentiated cell to a pluripotent state.

Epimorphosis

Morgan's term for regeneration using cellular proliferation.

Morphyllaxis

Morgan's term for regeneration using existing material in the animal, without relying on proliferation.

Lineage tracing

Tracing the progeny and fate of a population of cells using permanent labelling.

Schwann cells

Cells that surround and envelope neurons in myelin sheaths, allowing for proper conduction along the nerve.

Lateral plate mesoderm

A developmental division of mesoderm that gives rise to tendon, bone, connective tissue and dermis within the vertebrate limb.

Multinucleated myofibres

Syncytial muscle fibres formed from many muscle progenitors that fuse together to generate a single fibre with many nuclei.

Satellite cells

PAX7+ muscle stem cells that reside next to muscle fibres and mediate muscle regeneration in many vertebrate species.

Sarcomere apparatus

Actin, myosin and associated proteins within mature muscle fibres that are organized in such a way that they can move relative to each other to produce muscle contractions.

Myelin

An electrically insulating sheath provided by Schwann cell membranes that surrounds axons.

Linker histone

A histone that is responsible for stabilizing the complex of DNA wrapped around histones that forms nucleosomes.

Somatic cell nuclear transfer

(SCNT). A technique whereby nuclei from differentiated cells are transplanted into oocytes. These nuclei are reprogrammed to a pluripotent state and can, ultimately, generate a new organism.

Pluripotency factors

The OCT3/4, SOX2, KLF4 and MYC (OSKM) transcription factors that can induce differentiated cells to reprogramme into induced pluripotent stem cells. Also known as Yamanaka factors.

Pancreatic islets of Langerhans

Endocrine cells in the pancreas that are responsible for producing the hormones used for glucose management.

Glucagon

A hormone secreted by pancreatic α-cells that increases serum glucose levels.

Somatostatin

A hormone secreted by pancreatic δ-cells that inhibits the secretion of other pancreatic hormones.

Metaplasia

Changes in tissue whereby one cell type is replaced by another, often associated with increased cancer risk.

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Merrell, A., Stanger, B. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 17, 413–425 (2016). https://doi.org/10.1038/nrm.2016.24

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