1: Blood and lymphatic systems are segregated by the FLCN tumor suppressor
Science of the Month - February 2021
Nature Communications. 2020 December 9. doi: 10.1038/s41467-020-20156-6
Ikue Tai-Nagara, Yukiko Hasumi, Dai Kusumoto, Hisashi Hasumi, Keisuke Okabe, Tomofumi Ando, Fumio Matsuzaki, Fumiko Itoh, Hideyuki Saya, Chang Liu, Wenling Li, Yoh-suke Mukouyama, W. Marston Linehan, Xinyi Liu, Masanori Hirashima, Yutaka Suzuki, Shintaro Funasaki, Yorifumi Satou, Mitsuko Furuya, Masaya Baba & Yoshiaki Kubota
Blood vessels and lymphatic vessels form separate networks throughout the body, each performing its own unique functions. The two form independent networks without any connection until their final confluence at the venous angle in the neck. However, the structures of blood vessels, especially veins, and lymphatic vessels are very similar, and how they distinguish each other to ensure their independence has long been a question. In this study, we generated mice with a vascular endothelium-specific deletion of Flcn, a gene known to cause Birt-Hogg-Dubé syndrome, which is characterized by multiple pulmonary cysts and kidney cancer, and found that this resulted in anastomoses between blood and lymphatic vessels in various places. As for the mechanism, we found that Flcn negatively regulates the expression of Prox1, a master transcription factor for lymphatic development, in the venous endothelium. When this regulation is disrupted, 'lymphatic-like venous endothelial cells' are generated, causing the veins to recognize lymphatic vessels as targets for connection.
(Yoshiaki Kubota, Department of Anatomy, 79th graduating class)
2: Inhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury
Nature Communications . 2020 Nov 9;11(1):5666. doi: 10.1038/s41467-020-19491-5.
Mariko Hara-Chikuma, Manami Tanaka, Alan S. Verkman & Masato Yasui
Chronic hepatitis can progress to cirrhosis or liver cancer. To develop effective curative treatments for these conditions, there is a need to elucidate the mechanisms of pathological progression to cirrhosis and to search for new drugs. In this study, we revealed that aquaporin-3 (AQP3), expressed in immune cells called macrophages localized in the liver, plays an important role in the pathogenesis of hepatitis and cirrhosis. In a mouse model of hepatitis, AQP3-deficient mice showed reduced symptoms of acute and chronic hepatitis compared to wild-type mice. We showed that in macrophages lacking AQP3, cell activation that occurs during the development of liver injury is suppressed, thereby reducing chronic inflammation and fibrosis in the liver. Furthermore, we established the world's first monoclonal antibody that inhibits AQP3 and confirmed that administration of the AQP3 antibody suppresses the onset of hepatitis in mice. In the future, we expect to contribute to the development of new treatments for hepatitis and cirrhosis by further investigating the role of AQP3 in the pathological progression of these diseases and by developing AQP3 antibodies and inhibitors.
(Masato Yasui, Department of Pharmacology, 68th graduating class)
3:Anti-senescent drug screening by deep learning-based morphology senescence scoring
Nature Communications.
2021 Jan 11;12(1):257. doi: 10.1038/s41467-020-20213-0
Dai Kusumoto, Tomohisa Seki, Hiromune Sawada, Akira Kunitomi, Toshiomi Katsuki, Mai Kimura, Shogo Ito, Jin Komuro, Hisayuki Hashimoto, Keiichi Fukuda & Shinsuke Yuasa
In recent years, advances in artificial intelligence are expected to solve various problems in the field of medical sciences. In this paper, we developed a system (Deep-SeSMo) that uses convolutional neural networks, a type of artificial intelligence technology specializing in image analysis, to evaluate the degree of cellular senescence from microscope images of cultured vascular endothelial cells alone. Furthermore, by applying this system, we screened compounds and identified drug candidates that suppress the senescence of vascular endothelial cells. Previously, compound screening required the use of molecular biological methods to assess the pathological state of cells. However, the newly developed Deep-SeSMo can perform an evaluation in just 0.1 milliseconds per image simply by capturing a microscope image, enabling faster, simpler, and more reliable drug discovery screening than before. Application of this research is expected to lead to the development of new therapeutic drugs that suppress vascular aging.
(Dai Kusumoto, Department of Internal Medicine (Cardiology) / Center for Preventive Medicine, 86th graduating class)
Other Publications
1: Primary cilia safeguard cortical neurons in neonatal mouse forebrain from environmental stress-induced dendritic degeneration
PNAS . nuary 5, 2021 118 (1) e2012482118; DOI: 10.1073
Seiji Ishii, Toru Sasaki, Shahid Mohammad, Hye Hwang, Edwin Tomy, Fahad Somaa, Nobuyuki Ishibashi, Hideyuki Okano, Pasko Rakic, Kazue Hashimoto-Torii, and Masaaki Torii
2: Advances in the diagnosis and treatment of dry eye.
Progress in Retinal and Eye Research . 2020;78.
Kojima T, Dogru M, Kawashima M, Nakamura S, Tsubota K.