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

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.

The small and large intestine contain transcriptionally related mesenchymal stromal cell subsets that derive from embryonic Gli1+ mesothelial cells

“…1F, Fig. S1G), supporting previous findings (Kurahashi et al, 2013;Bahar Halpern et al, 2020;Brügger et al, 2020;Hong et al, 2020;McCarthy et al, 2020).…”

“…S1C). To determine how these clusters might relate to those identified in other, recently published scRNA-seq studies of small intestinal MSC (Hong et al, 2020;McCarthy et al, 2020), DEGs from the previous MSC subsets were overlaid with our scRNA-seq dataset (Fig. S1D).…”

“…The intestinal lamina propria (LP) contains a large population of tissue resident mesenchymal stromal cells (MSC) that include fibroblasts (FB), pericytes (PC) and smooth muscle cells (SMCs) that play an essential role in intestinal homeostasis (Degirmenci et al, 2018;Kinchen et al, 2018;Shoshkes-Carmel et al, 2018;Brügger et al, 2020;Hong et al, 2020;McCarthy et al, 2020;Wu et al, 2021). For example, intestinal FB are major producers of extracellular matrix proteins that help provide structure to the mucosa (Furuya and Furuya, 2007;Roulis and Flavell, 2016).…”

The asymmetric Pitx2 regulates intestinal muscular-lacteal development and protects against fatty liver disease

“…It is well established that lymphatic homeostasis and function is regulated in part in a non-cell autonomous manner by the adjacent microenvironment [35, 37, 83, 100, 101]. Because ROS can act on surrounding cells with [102, 103] or without [104] diffusion, our data support this model and raise the possibility that ROS-generating axial SMCs can influence cell behavior of the adjacent lacteal including the formation of lacteal filopodia extensions.…”

“…Therefore, Tbx18+ cells within the right dorsal mesentery may provide an additional source of axial SMCs, functionally distinct from those on the left. Similar heterogeneity has recently been demonstrated within the villous fibroblast compartment, highlighting the importance of the dynamic paracrine milieu of the lamina propria to the overall integrity and function of intestinal lymphatic vasculature [83].…”