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.
Highlights
Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis
The surface area and length of lacteals increased by ∼1.6 and ∼1.3-fold, respectively, while villi width was reduced by ∼23% in all portions of small intestine in Lats1/2iΔPβC mice compared with WT; villi length was not significantly changed (Fig. 1b, c)
Our approach to block VEGFR2 signaling by α-VEGFR2 blocking antibody, DC101 (50 mg/kg every alternative day for 2 weeks), could only partially restore the aberrant lacteal sprouting and branching, but almost no changes were observed in the number of lacteal Prox1+ lymphatic endothelial cells (LECs) and lacteal junctional transition compared with IgG control in Lats1/2iΔPβC mice (Supplementary Fig. 8a–f). These results indicate that activation of vascular endothelial growth factor (VEGF)-C–VEGFR3 signaling plays a greater role than VEGFR2 signaling in aberrant lacteal sprouting and branching led by YAP and TAZ (YAP/TAZ) hyperactivation in PDGFRβ+ IntSCs
Summary
Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. 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. A lacteal is surrounded by the villus stroma, which is composed of capillaries, pericytes, smooth muscle cells (SMCs), fibroblasts, immune cells, and extracellular matrix residing under the rapidly renewing intestinal epithelial cells[1,2,3] In this milieu, a subset of SMCs has been suggested as an important source of VEGF-C for lacteal maintenance[5]. Our results show that certain subsets of fibroblasts surrounding a lacteal secrete VEGF-C upon YAP/TAZ activation These findings propose the novel and dynamic regulatory mechanism of lacteal maintenance and function by distinct subsets of fibroblasts, which constitute the peri-lacteal microenvironment
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