Convergent flow-mediated mesenchymal force drives embryonic foregut constriction and splitting

Rui Yan, Ludwig A. Hoffmann, Panagiotis Oikonomou, Deng Li, ChangHee Lee, Hasreet K. Gill, Alessandro Mongera, Nandan L. Nerurkar, L. Mahadevan () and Clifford J. Tabin ()
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Rui Yan: Harvard Medical School, Department of Genetics, Blavatnik Institute
Ludwig A. Hoffmann: Harvard University, School of Engineering and Applied Sciences
Panagiotis Oikonomou: Columbia University, Department of Biomedical Engineering
Deng Li: Northeastern University, Department of Bioengineering
ChangHee Lee: Harvard Medical School, Department of Genetics, Blavatnik Institute
Hasreet K. Gill: Harvard Medical School, Department of Genetics, Blavatnik Institute
Alessandro Mongera: University College London, Department of Cell & Developmental Biology
Nandan L. Nerurkar: Columbia University, Department of Biomedical Engineering
L. Mahadevan: Harvard University, School of Engineering and Applied Sciences
Clifford J. Tabin: Harvard Medical School, Department of Genetics, Blavatnik Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The transformation of a two-dimensional epithelial sheet into various three-dimensional structures is a critical process in generating the diversity of animal forms. Previous studies of epithelial folding have revealed diverse mechanisms driven by epithelium-intrinsic or -extrinsic forces. Yet little is known about the biomechanical basis of epithelial splitting, which involves extreme folding and eventually a topological transition breaking the epithelial tube. Here, we leverage tracheal-esophageal separation (TES), a critical and highly conserved morphogenetic event during tetrapod embryogenesis, as a model system for interrogating epithelial tube splitting. We identify an evolutionarily conserved, compressive force exerted by the mesenchyme surrounding the epithelium, as being necessary to drive epithelial constriction and splitting. The compressive force is mediated by localized convergent flow of mesenchymal cells towards the epithelium. Sonic hedgehog (SHH) secreted by the epithelium functions as an attractive cue for mesenchymal cells. Removal of the mesenchyme, inhibition of cell migration, or loss of SHH signaling all abrogate TES, which can be rescued by externally applied pressure. These results unveil the biomechanical basis of epithelial splitting and suggest plausible mesenchymal origins of tracheal-esophageal birth defects.

Date: 2025
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DOI: 10.1038/s41467-025-65644-9

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