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Epithelial–mesenchymal transition in tissue repair and degeneration

Nature Reviews Molecular Cell Biology (2024)Cite this article

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Abstract

Epithelial–mesenchymal transitions (EMTs) are the epitome of cell plasticity in embryonic development and cancer; during EMT, epithelial cells undergo dramatic phenotypic changes and become able to migrate to form different tissues or give rise to metastases, respectively. The importance of EMTs in other contexts, such as tissue repair and fibrosis in the adult, has become increasingly recognized and studied. In this Review, we discuss the function of EMT in the adult after tissue damage and compare features of embryonic and adult EMT. Whereas sustained EMT leads to adult tissue degeneration, fibrosis and organ failure, its transient activation, which confers phenotypic and functional plasticity on somatic cells, promotes tissue repair after damage. Understanding the mechanisms and temporal regulation of different EMTs provides insight into how some tissues heal and has the potential to open new therapeutic avenues to promote repair or regeneration of tissue damage that is currently irreversible. We also discuss therapeutic strategies that modulate EMT that hold clinical promise in ameliorating fibrosis, and how precise EMT activation could be harnessed to enhance tissue repair.

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Fig. 1: EMT processes in development and disease.
Fig. 2: Molecular mechanisms of transcriptional EMT regulation.
Fig. 3: EMT and tissue repair.
Fig. 4: Adult EMT: repair versus degeneration.
Fig. 5: Targeting EMT to attenuate fibrosis.
Fig. 6: Transient EMT activation can promote repair process in non-regenerative tissues.

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Acknowledgements

The authors thank all members of the Nieto laboratory for discussion and comments on the manuscript. This work was supported by grants from the Spanish Ministries of Science and Innovation (MCI PID2021-125682NB-I00), from the AECC Scientific Foundation (FC_AECC PROYE19073NIE), Instituto de Salud Carlos III (CIBERER, CB19/07/00038 to M.A.N.) and Generalitat Valenciana (Prometeo 2021/45) to M.A.N., who also acknowledges financial support from the Spanish State Research Agency, through the Severo Ochoa Program for Centres of Excellence in R&D (CEX2021-001165-S). K.K.Y. holds an investigator contract from the AECC Scientific Foundation (Ayudas AECC investigador 2022).

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Authors and Affiliations

  1. Instituto de Neurociencias (CSIC-UMH), Sant Joan d’Alacant, Spain

    Khalil Kass Youssef & M. Angela Nieto

  2. CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain

    M. Angela Nieto

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  1. Khalil Kass Youssef
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Supplementary information

Glossary

Apicobasal polarity

A term that alludes to the polarization of epithelial cells into a basal pole that faces and adheres to the basal membrane and an apical pole that faces the outside of the body or the lumen of internal cavities.

Blastema

Mass of proliferative and undifferentiated progenitor-like cells that appears in response to injury to initiate tissue repair.

Cell senescence

Irreversible cell cycle arrest.

Clara cells

Population of non-ciliated secretory cells in the lung bronchiolar epithelium that have an essential role in repair after injury.

Embryo tail bud

Mass of embryonic undifferentiated, multipotent and proliferative cells that resides in the most caudal part of chordate embryos.

Ephrin B1

Ephrin B1, encoded by the EFNB1 gene, is a member of the ephrin family, ligands of EPH-related receptor tyrosine kinases.

Epimorphosis

The dedifferentiation of somatic adult cells into phenotypes reminiscent of those that occur during embryonic development in response to injury and their extensive cell proliferation before undergoing redifferentiation to replace the damaged tissues.

Ferroptosis

Iron-dependent programmed cell death induced by the accumulation of lipid peroxides at the cell membrane.

Genetic fate mapping

Stable and inheritable labelling of a cell (or group of cells). Genetic fate mapping is used in embryonic development to define cell lineages and to define the cells of origin in cancer evolution.

Inflammasome

Cytoplasmic multiprotein complex that senses both endogenous and exogenous stimuli and, as a response, mediates proteolytic cleavage and secretion of pro-inflammatory cytokines.

Leader cells

Term used to define cells located at the edge of neural crest or other migratory streams, which can instruct migration directionality.

Myofibroblasts

Specialized fibroblasts with high contractile capacity. Myofibroblasts initially form to protect adult tissues after stress and damage, but during chronic damage they accumulate and cause excessive extracellular matrix deposition, scarring and tissue degeneration.

Octamer-binding transcription factor 4

(OCT4). A transcription factor that promotes self-renewal and the maintenance of pluripotency in embryonic stem cells or multipotency in some progenitors. It is also one of the four ‘Yamaka factors’, used for somatic cell reprogramming into induced pluripotent stem cells.

Pluripotency

The ability of given cells to give rise to multiple cell types. It is commonly used to refer to the ability of a cell to give rise to cells of the three primary germ cell layers: ectoderm, mesoderm and endoderm.

Pre-eclampsia

A disorder characterized by persistent high blood pressure during pregnancy, leading to multiple organ dysfunction. Untreated or severe pre-eclampsia can lead to serious complications to the mother and fetus.

Primitive streak

A structure that forms in the early embryo amniotes in which multiple epiblast cells ingress to allow gastrulation and formation of the three germ layers.

Trophoblasts

Cells that form the outer layer of the blastocyst, which has an essential role in embryo implantation and placenta formation.

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Youssef, K.K., Nieto, M.A. Epithelial–mesenchymal transition in tissue repair and degeneration. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00733-z

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