Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, 34141, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
Nat Commun. 2020 Jan 24;11(1):519. doi: 10.1038/s41467-020-14293-1.
Fibroblastic reticular cells (FRCs) are immunologically specialized myofibroblasts of lymphoid organ, and FRC maturation is essential for structural and functional properties of lymph nodes (LNs). Here we show that YAP and TAZ (YAP/TAZ), the final effectors of Hippo signaling, regulate FRC commitment and maturation. Selective depletion of YAP/TAZ in FRCs impairs FRC growth and differentiation and compromises the structural organization of LNs, whereas hyperactivation of YAP/TAZ enhances myofibroblastic characteristics of FRCs and aggravates LN fibrosis. Mechanistically, the interaction between YAP/TAZ and p52 promotes chemokine expression that is required for commitment of FRC lineage prior to lymphotoxin-β receptor (LTβR) engagement, whereas LTβR activation suppresses YAP/TAZ activity for FRC maturation. Our findings thus present YAP/TAZ as critical regulators of commitment and maturation of FRCs, and hold promise for better understanding of FRC-mediated pathophysiologic processes.
纤维母细胞网状细胞（FRCs）是淋巴器官中具有免疫特异性的肌成纤维细胞，FRC 的成熟对于淋巴结（LNs）的结构和功能特性至关重要。在这里，我们表明 Hippo 信号的最终效应因子 YAP 和 TAZ（YAP/TAZ）调节 FRC 的定型和成熟。FRC 中 YAP/TAZ 的选择性耗竭会损害 FRC 的生长和分化，并损害 LNs 的结构组织，而 YAP/TAZ 的过度激活则增强了 FRC 的肌成纤维细胞特征，并加重了 LN 纤维化。在机制上，YAP/TAZ 与 p52 的相互作用促进了趋化因子的表达，这对于 LTβR 参与之前 FRC 谱系的定型是必需的，而 LTβR 的激活则抑制了 FRC 成熟过程中的 YAP/TAZ 活性。因此，我们的研究结果表明 YAP/TAZ 是 FRC 定型和成熟的关键调节因子，为更好地理解 FRC 介导的病理生理过程提供了希望。
