1: Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1
Science of the Month - February 2020
Nat Immunol.
Tetsuo Hasegawa, Junichi Kikuta, Takao Sudo, Yoshinobu Matsuura, Takahiro Matsui1, Szandor Simmons, Kosuke Ebina, Makoto Hirao, Daisuke Okuzaki, Yuichi Yoshida, Atsushi Hirao, Vladimir V. Kalinichenko, Kunihiro Yamaoka, Tsutomu Takeuchi, and Masaru Ishii
Osteoclasts, unique multinucleated cells responsible for bone resorption, cause pathological bone destruction in arthritis. However, there have been no reports of detailed analyses of the "inflamed synovium," the main site of this lesion, in mouse models. In this study, we isolated the inflamed synovium from the bone-synovium junction where bone erosion occurs in arthritis and revealed that a macrophage subset, CX3CR1hiLy6CintF4/80hiI-A/I-E+, which is absent in the bone marrow, possesses a marked ability to differentiate into osteoclasts. We named this cell fraction Arthritis-associated osteoclastogenic macrophage (AtoM). Using a CX3CR1-EGFP/TRAP-tdTomato reporter system, we showed that AtoMs and mature osteoclasts originate from bone marrow cells, not from synovial resident macrophages, and that they differentiate significantly into osteoclasts upon co-stimulation with TNF and RANKL. Comprehensive transcriptome analysis showed that while CX3CR1loLy6Chi cells that have infiltrated the synovium from the blood highly express inflammatory cytokines and Vegfa, AtoMs highly express osteoclast marker genes, suggesting that Foxm1 is involved in the ability to differentiate into osteoclasts. Single-cell analysis of AtoMs revealed that about 10% of the cells further highly express osteoclast marker genes such as Acp-5, Ctsk, and Atp6v0d2. It became clear that this cell population, consisting of approximately 800 cells per individual, differentiates into pathogenic osteoclasts in situ (Figure). In the future, the development of new therapeutic strategies targeting these pathogenic osteoclasts is expected.
(Tetsuo Hasegawa, 90th Graduating Class, Department of Rheumatology and Clinical Immunology / Studying at Osaka University)
2: Chromosome Engineering of Human Colon-Derived Organoids to Develop a Model of Traditional Serrated Adenoma
Gastroenterology.
2019 Oct 14. pii: S0016-5085(19)41446-7.
Kenta Kawasaki, Masayuki Fujii, Shinya Sugimoto, Keiko Ishikawa, Mami Matano, Yuki Ohta, Kohta Toshimitsu, Sirirat Takahashi, Naoki Hosoe, Shigeki Sekine, Takanori Kanai1, Toshiro Sato
Tumors that arise in our bodies originate from normal tissues and are characterized by various morphological changes, but how are these produced? We have been conducting research to grow tumor tissues obtained from patients as three-dimensional cultured tissues called "organoids" in culture dishes, and have studied what kind of genomic abnormalities are involved in unique tumor tissue morphology. This time, we focused on a colorectal tumor that shows a characteristic histological image called traditional serrated adenoma (TSA). The most difficult part of this research was that TSA is characterized by chromosomal translocations, which are rare for colorectal tumors. While previous CRISPR/Cas9 genome editing technology has excelled at gene disruption, there have been no reports of successful chromosome editing in human tissue stem cells. Through technological optimization, we succeeded in artificially introducing the BRAF mutation and the RSPO2/3 fusion gene found in TSA. However, the artificial tumor showed a different histological image from a genuine TSA. By forcibly expressing Gremlin1, which suppresses the BMP signal—a finding obtained from re-examining clinical samples—we succeeded in inducing a histological image close to that of TSA. This technology is considered pioneering research for "Precise disease modeling" originating from normal cells and is expected to become the foundation for elucidating the causes of various diseases through genome and chromosome editing.
(Kenta Kawasaki, 90th Graduating Class, Department of Gastroenterology and Hepatology; Toshiro Sato, 76th Graduating Class, Organoid medical sciences)
Other Published Papers
1: Ropinirole, a New ALS Drug Candidate Developed Using iPSCs.
Trends Pharmacol Sci.
2020 Jan 8. pii: S0165-6147(19)30274-3.
Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S.
2: Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.
Lancet Oncology.
2019;20(11):1506-1517. DOI: 10.1016/s1470-2045(19)30626-6
Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y.
3: Prognostic index for patients with relapsed or refractory acute myeloid leukemia who underwent hematopoietic cell transplantation: a KSGCT multicenter analysis.
Leukemia.
2019;33(11):2610-2618. DOI: 10.1038/s41375-019-0494-9
Tachibana T, Kanda J, Ishizaki T, Najima Y, Tanaka M, Doki N, Fujiwara S, Kimura S, Onizuka M, Takahashi S, Saito T, Mori T, Fujisawa S, Sakaida E, Matsumoto K, Aotsuka N, Goto M, Watanabe R, Shono K, Usuki K, Tsukada N, Kanamori H, Kanda Y, Okamoto S.
4: p63 is a cereblon substrate involved in thalidomide teratogenicity.
Nature Chemical Biology.
2019;15(11):1077-+. DOI: 10.1038/s41589-019-0366-7
Asatsuma-Okumura T, Ando H, De Simone M, Yamamoto J, Sato T, Shimizu N, Asakawa K, Yamaguchi Y, Ito T, Guerrini L, Handa H.
5: A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2.
Nature Communications.
2019;10. DOI: 10.1038/s41467-019-13640-1
Tamura R, Fujioka M, Morimoto Y, Ohara K, Kosugi K, Oishi Y, Sato M, Ueda R, Fujiwara H, Noji S, Oishi N, Ogawa K, Kawakami Y, Ohira T, Yoshida K, Toda M.