Intestinal Tissue Mechanics Regulate Angiogenesis and Stem Cell Proliferation via Vascular Piezo

Cordero, J. B.; Phillips, J. A.; Perochon, J.; Johnson, C. T.; Walker, M.; Nixon, C.; Hughes, M.; Barros Carvalho, A.; Yu, Y.; Mitchell, L.; Blyth, K.; Vassalli, M.

doi:10.1101/2025.04.16.649133

bioRxiv · 10.1101/2025.04.16.649133

Intestinal Tissue Mechanics Regulate Angiogenesis and Stem Cell Proliferation via Vascular Piezo

Cordero, J. B.·Phillips, J. A.·Perochon, J.·Johnson, C. T.·Walker, M.·Nixon, C.·Hughes, M.·Barros Carvalho, A.·Yu, Y.·Mitchell, L.·Blyth, K.·Vassalli, M.

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Abstract

The vasculature is a prominent component of developmental and adult tissue microenvironments. How tissue specific characteristics and environmental states influence vascular biology and function, remains largely understudied. Using the fruit fly Drosophila melanogaster midgut and its associated vascular-like tracheal system, we discover reciprocal, mechanochemical interorgan communication between the adult intestine and its vascular microenvironment, which influences vascular and stem cell adaptations during intestinal regeneration. Mechanistically, apoptotic epithelial cells contribute to biomechanical remodelling of the regenerating midgut, which is associated with activation of Piezo in a subset of gut tracheal cells. Piezo drives activation of the mechanosensitive transcription factor Yorkie/YAP, leading to tracheal remodelling and intestinal stem cell proliferation. Furthermore, we identify a conserved role of mammalian vascular Piezo1 influencing remodelling of the intestinal crypt vasculature, and intestinal regeneration upon DNA damage and inflammation in mice. Our cross-species in vivo study reveals the presence of biomechanically distinct compartments in the regenerative intestine and identifies mechanosensory interorgan signalling, which contributes to intestinal regeneration through the vascular-stem cell niche. Furthermore, our work highlights the importance of studying tissue- and context-specific vascular biology to better understand intestinal compartmentalization, plasticity, and the complexity of tissue/vasculature interactions within a living organ.

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Cordero, J. B., Phillips, J. A., Perochon, J., Johnson, C. T., Walker, M., Nixon, C., Hughes, M., Barros Carvalho, A., Yu, Y., Mitchell, L., Blyth, K., Vassalli, M.. 2025-04-16. Intestinal Tissue Mechanics Regulate Angiogenesis and Stem Cell Proliferation via Vascular Piezo. https://doi.org/10.1101/2025.04.16.649133

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