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  • Review Article
  • Published:

Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies

Key Points

  • For more then half a century, C. H. Waddington's metaphor of a marble rolling down a landscape that segregates into different grooves has served as a sophisticated illustration of cell specification during development. However, some shortcomings emerge when trying to apply such a model to recent reprogramming and cell fate conversion studies.

  • This Review discusses the current state of the art in direct cell fate conversion and also presents a new 'epigenetic disc' model. This model provides an alternative hierarchy-free landscape for modelling cell programming and accomodates new findings in this rapidly developing field.

  • Recent studies demonstrate that direct cell conversion is not limited to cell types from the same germ layer. With a set of just a few transcription factors and/or microRNAs, direct cell conversion can be achieved between several germ layers. Yet, parameters for validating such conversion processes are still to be defined. They include conversion efficiency and identity, stability, functionality and safety of the converted cell types.

  • The recent advances in cell fate conversion have raised exciting new questions in the field and have paved the way for new research studies, which address the induction of distinct cellular subtypes and expandable progenitor cells, how to enhance conversion efficiency and how to translate this approach to an in vivo scenario.

Abstract

For decades, Waddington's concept of the 'epigenetic landscape' has served as an educative hierarchical model to illustrate the progressive restriction of cell differentiation potential during normal development. While still being highly valuable in the context of normal development, the Waddington model falls short of accommodating recent breakthroughs in cell programming. The advent of induced pluripotent stem (iPS) cells and advances in direct cell fate conversion (also known as transdifferentiation) suggest that somatic and pluripotent cell fates can be interconverted without transiting through distinct hierarchies. We propose a non-hierarchical 'epigenetic disc' model to explain such cell fate transitions, which provides an alternative landscape for modelling cell programming and reprogramming.

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Figure 1: Challenging Waddington's epigenetic landscape model.
Figure 2: Direct conversion of somatic cells.
Figure 3: The epigenetic disc model.

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Acknowledgements

Work in the laboratory of O. B. is supported by the European Union (FP7-HEALTH-2007-B-22943-NeuroStemCell and FP7-HEALTH-2010-266753-SCR&Tox, COLIPA; to O.B.), the Federal Ministry of Education and Research (BMBF; grants 01GS0860, 01GN1008C, 01GN1009B, 0315799; to O.B.; ERA-Net for Research Programmes on Rare Diseases 01GM1309A; to P.K.), BIO.NRW (project StemCellFactory; to O.B. and P.K.), the Hertie Foundation (to O.B.), the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (to J.L. and P.K.) and BONFOR (to J.L.).

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FURTHER INFORMATION

Institute of Reconstructive Neurobiology

Glossary

Anlage

The initial clustering of embryonic cells from which a part of an organ, or the whole organ, develops.

Exocrine cells

Cells that secrete hormones, factors or other material.

Type I diabetes

A variant of diabetes that is caused by an autoimmune reaction against insulin-producing cells; previously also known as juvenile diabetes.

Ground state

A physics and chemistry term that denotes the state of having the least energy of all the possible states. This term was recently adopted in cell biology to denote the most primordial or authentic state, or differentiation stage (such as ground state pluripotency), of a cell.

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Ladewig, J., Koch, P. & Brüstle, O. Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies. Nat Rev Mol Cell Biol 14, 225–236 (2013). https://doi.org/10.1038/nrm3543

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