Sung Yong Choi1,2,11, Hosung Bae3,11, Sun-Hye Jeong4,11, Intae Park1, Hyunsoo Cho1, Seon Pyo Hong1, Da-Hye Lee4, Choong-kun Lee1,2, Jin-Sung Park1, Sang Heon Suh1,2, Jeongwoon Choi1,3, Myung Jin Yang1,3, Jeon Yeob Jang5, Lucas Onder6, Jeong Hwan Moon7, Han-Sin Jeong8, Ralf H. Adams9, Jin-Man Kim10, Burkhard Ludewig6, Joo-Hye Song1, Dae-Sik Lim4,* & Gou Young Koh1,2,3,*
1 Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
3 Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea.
4 Department of Biological Science, KAIST, Daejeon 34141, Republic of Korea.
5 Department of Otorhinolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
6 Institute of Immunobiology, Kantossipital St. Gallen, St. Gallen 9007, Switzerland.
7 Department of Otorhinolaryngology - Head and Neck Surgery, Dankook University College of Medicine, Cheonan 31116, Republic of Korea.
8 Department of Otorhinolaryngology - Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
9 Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and Faculty of Medicine, University of Münster, Münster MD-48149, Germany.
10 Department of Pathology, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea.
11 These authors contributed equally: Sung Yong Choi, Hosung Bae, Sun-Hye Jeong
*Correspondence to Dae-Sik Lim or Gou Young Koh
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.