Study on the lymph node microenvironment and thyroid remodeling

Abstract

Part I. Hippo Pathway Regulates Maturation and Integrity of Fibroblastic Reticular Cells in Lymph Nodes Fibroblastic reticular cells (FRCs) serve as scaffolding microarchitecture for lymph nodes (LNs) and respond dynamically to various stimuli. However, the regulatory signaling path-ways that govern the structural and functional adaptations of FRCs are poorly understood. Here, I show that Hippo signaling is a dominant regulator for maturation and for maintaining FRC integrity in LNs. YAP, a transcriptional co-activator and end effector of Hippo signaling, was highly enriched in FRCs, while highly activated YAP was detected in the FRCs of LNs harboring metastases. Genetic hyperactivation of YAP/TAZ in FRCs led to disruption of the LN microarchitecture by augmenting FRC myofibrosis, causing impaired lymphocyte com-partmentalization and weakened immune responses. Moreover, genetic deletion of YAP/TAZ in FRCs also disrupted the LN reticular network, leading to an impaired immune responsive-ness. Together, these results demonstrate indispensable roles for YAP/TAZ in the maturation and maintenance of FRCs in LNs.

Part II. VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angi-ofollicular unit in normal state and during goitrogenesis Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a criti-cal component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poor-ly understood. Here, my genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity. Notably, blockade of VEGF-A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hy-pertrophy, which led to the reduction of thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with de-creases in thyrotropin-responsive genes in goitrogen-fed thyroids. Collectively, these findings establish follicular VEGF-A-vascular VEGFR2 axis as a main regulator for thyrotropin-dependent thyroid angiofollicular remodeling and goitrogenesis.