Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi

Seon Pyo Hong, Myung Jin Yang, Hyunsoo Cho, Intae Park, Hosung Bae, Kibaek Choe, Sang Heon Suh, Ralf H. Adams, Kari Alitalo, Daesik Lim and Gou Young Koh ()
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Seon Pyo Hong: Center for Vascular Research, Institute for Basic Science (IBS)
Myung Jin Yang: Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST)
Hyunsoo Cho: Center for Vascular Research, Institute for Basic Science (IBS)
Intae Park: Center for Vascular Research, Institute for Basic Science (IBS)
Hosung Bae: Center for Vascular Research, Institute for Basic Science (IBS)
Kibaek Choe: Graduate School of Nanoscience and Technology, KAIST
Sang Heon Suh: Center for Vascular Research, Institute for Basic Science (IBS)
Ralf H. Adams: Max Planck Institute for Molecular Biomedicine, and University of Münster
Kari Alitalo: Translational Cancer Biology Program and Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki
Daesik Lim: KAIST
Gou Young Koh: Center for Vascular Research, Institute for Basic Science (IBS)

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRβ+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.

Date: 2020
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DOI: 10.1038/s41467-020-17886-y

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