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Signal control during tissue regeneration in adult animals

Nature Reviews Molecular Cell Biology volume 27, pages 316–335 (2026)Cite this article

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Abstract

Tissue regeneration has historically been the subject of intense scientific scrutiny, from basic biology to applications in regenerative medicine. Use of model organisms and cutting-edge technologies have uncovered various mechanisms of regeneration, but understanding how signals are regulated spatiotemporally to renew lost structures at scale remains a challenge. Recent insights into chromatin structure and enhancer regulation, immune–tissue crosstalk, bioelectric and metabolic cues and quantitative modelling are broadening and reshaping our understanding of how tissues repair and renew. The evolution of cutting-edge tools for in vivo profiling and tracking of single cells is providing unprecedented dynamic views of regeneration across scales. Here, we synthesize the current knowledge of signal control in regeneration, with emphasis on conceptual advances, technical innovations and future directions for a more quantitative understanding of regenerative biology.

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Fig. 1: Source of new cells during tissue regeneration.
Fig. 2: Gene regulation mechanisms in tissue regeneration.
Fig. 3: Microenvironment and metabolic state regulate regeneration outcomes.
Fig. 4: Positional memory and scaling mechanisms to regulate regeneration.
Fig. 5: Probing aspects of regeneration using quantitative approaches.

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Acknowledgements

The authors thank P. Murawala, A. Rich, C.-H. Chen and A. De Simone for comments on the manuscript. The authors acknowledge postdoctoral funding support from Duke Center for Advanced Genome Technologies to S.B. and from Jane Coffin Childs Memorial Fund for Medical Research and the Duke Regeneration Center to R.D.; an award in Innovative Stem Cell Science from the Shipley Foundation, Inc. to S.D.-T.; and grants from NIH to S.D.T. (R01 AR076342) and K.D.P. (R35 HL150713, R01 AR076342, R01 HD115266, R01 HD105033 and R21HD116006).

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Authors and Affiliations

  1. Morgridge Institute for Research, Madison, WI, USA

    Sushant Bangru & Kenneth D. Poss

  2. Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, USA

    Sushant Bangru & Kenneth D. Poss

  3. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA

    Sushant Bangru, Rocky Diegmiller & Stefano Di Talia

  4. Center for Quantitative Living Systems, Duke University School of Medicine, Durham, NC, USA

    Rocky Diegmiller & Stefano Di Talia

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  1. Sushant Bangru
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  2. Rocky Diegmiller
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Contributions

S.B. and R.D. researched data for the article. All authors contributed substantially to discussion of the content. S.B. and R.D. wrote the article. S.D.T. and K.D.P. supervised the writing, reviewed and edited the manuscript before submission.

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Correspondence to Stefano Di Talia or Kenneth D. Poss.

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Glossary

Cellular hypertrophy

Increase in cell size (rather than number), often as a compensatory mechanism during tissue regeneration.

Clonogenic potential

The ability of a single cell to proliferate and form colonies, indicating self-renewal and differentiation capacity.

Condensates

Membrane-less, phase-separated molecular assemblies that compartmentalize biomolecules such as RNA and proteins to regulate gene expression and cell function.

Fibrosis

The formation of excess fibrous connective tissue during healing that can impede regeneration and lead to scarring.

Hippo pathway

A conserved signalling cascade that regulates organ size, cell proliferation and regeneration, often by modulating transcriptional co-activators such as YAP/TAZ.

INo80 chromatin-remodelling complex

A multisubunit protein complex that alters nucleosome positioning to regulate gene expression.

Lobes

Distinct anatomical subdivisions of an organ, such as two main lobes in human liver or the left and right lobes in human lungs.

Morphogens

A class of signalling molecules that can be present in concentration gradients that lead to differential cell fate specification in developing and growing tissues.

Quiescence

A reversible, non-dividing state in which cells remain metabolically active but do not proliferate.

Region capture micro-C

A high-resolution chromatin conformation assay that maps enhancer–promoter interactions by capturing localized 3D genome architecture.

RNA-binding protein

(RBP). Proteins that bind RNA molecules to regulate their splicing, transport, translation and/or stability during regeneration and homeostasis.

Scarring

Permanent deposition of fibrotic tissue following injury that may limit or replace normal tissue regeneration.

Stemness

The qualities that define a stem cell, including the abilities to self-renew and give rise to differentiated progeny.

Topologically associating domains

(TADs). Genomic regions where DNA sequences physically interact more frequently with each other than with sequences outside the domain, influencing gene regulation.

Wave propagation

The spatial movement of the edge of an asymmetry, usually defined as the region between high and low concentrations of a molecule in a biological context.

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Bangru, S., Diegmiller, R., Di Talia, S. et al. Signal control during tissue regeneration in adult animals. Nat Rev Mol Cell Biol 27, 316–335 (2026). https://doi.org/10.1038/s41580-025-00917-1

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