1: SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production
Science of the Month - July 2024
Cell Stem Cell.
2024 May 14:S1934-5909(24)00176-0. doi: 10.1016/j.stem.2024.04.023. Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo
It is generally believed that stem cells decrease in number and decline in function with age. However, this conventional wisdom could not explain why hematopoietic stem cells (HSCs), which produce all blood cells, increase in number with age. In experiments using aged mice, our research team discovered that with aging, HSCs become resistant to various stresses that induce cell death, thereby gaining a survival advantage. Furthermore, it was found that in aged HSCs, SDHAF1, which increases the activity of mitochondrial respiratory chain complex II, accumulates. As a result, ATP production through oxidative phosphorylation is enhanced, improving resistance to cytotoxic stress. In humans, it was also confirmed that the accumulation of SDHAF1 in HSCs begins from middle age. Indeed, when SDHAF1 was overexpressed in young HSCs, metabolic changes and resistance to cell death similar to those in aged HSCs were observed. These research findings reveal that aged HSCs are not merely functionally declined cells but are, from an energy metabolism perspective, "strong" HSCs. Based on this knowledge, the development of new therapies to ameliorate age-related blood disorders is anticipated.
(Tohoku University / National Center for Global Health and Medicine, Keiyo Takubo (82))
2: Phase I/II Study of a VEGFR Vaccine in Patients with NF2-related Schwannomatosis.
J Clin Oncol .
2024 May 22:JCO2302376. doi: 10.1200/JCO.23.02376. Tamura R, Yamanobe Y, Fujioka M, Morimoto Y, Fukumura M, Nakaya M, Oishi Y, Sato M, Ueda R. Fujiwara H, Hikichi T, Noji S, Oishi N, Ozawa H, Ogawa K, Kawakami Y, Ohira T, Yoshida K, Toda M.
Neurofibromatosis type 2 (NF2-related schwannomatosis: NF2) is a genetic disorder characterized by bilateral vestibular schwannomas and the development of multiple tumors. It causes hearing impairment from a young age, progresses rapidly, and has a reported 10-year survival rate of 67%. Focusing on the high expression of vascular endothelial growth factor receptor (VEGFR) in NF2 tumor blood vessels and tumor cells, we initiated the development of a VEGFR1/2 peptide vaccine. Cytotoxic T lymphocytes (CTLs) activated by the vaccine target and destroy cells expressing VEGFR1/2. Furthermore, as CTLs persist in the body, long-term effects are expected. This is the world's first immunotherapy for NF2, and in clinical trials that began in 2016, we have obtained promising results regarding its safety and efficacy. We are currently formulating the VEGFR1/2 peptide vaccine and plan to start an investigator-initiated clinical trial soon. If we can demonstrate the effectiveness of the peptide vaccine against refractory benign tumors, it is expected to change existing treatment concepts. NF2 is a rare disease, and opportunities to focus on drug development are scarce. We will continue to make every effort to deliver this new treatment to NF2 patients as soon as possible.
(Department of Neurosurgery, Masahiro Toda (66), Ryota Tamura (89))
Other Published Papers
1: Near-Infrared II Photobiomodulation Preconditioning Ameliorates Stroke Injury via Phosphorylation of eNOS
Shinya Yokomizo, Timo Kopp, Malte Roessing, Atsuyo Morita, Seeun Lee, Suin Cho, Emiyu Ogawa, Eri Komai, Kazumasa Inoue, Masahiro Fukushi, Susanne Feil, Hyung-Hwan Kim, Denis E. Bragin, Dmitry Gerashchenko, Paul L. Huang, Satoshi Kashiwagi and Dmitriy N. Atochin
2: Aberrant CHCHD2-Associated Mitochondriopathy in Kii ALS/PDC Astrocytes
Acta Neuropathologica .
Nicolas Leventoux*; Satoru Morimoto*; Mitsuru Ishikawa; Shiho Nakamura; Fumiko Ozawa; Reona Kobayashi; Hirotaka Watanabe; Sopak Supaku; Satoshi Okamoto; Zhi Zhou; Hiroya Kobayashi; Chris Kato; Yoshifumi Hirokawa; Ikuko Aiba; Shinichi Takahashi; Shinsuke Shibata; Masaki Takao; Mari Yoshida; Fumito Endo; Koji Yamanaka; Yasumasa Kokubo†; Hideyuki Okano†,.
3: Three stepwise pH progressions in stratum corneum for homeostatic maintenance of the skin
Nat Commun .
2024 May 15;15(1):4062. doi: 10.1038/s41467-024-48226-z.
Keitaro Fukuda #, Yoshihiro Ito #, Yuki Furuichi #, Takeshi Matsui, Hiroto Horikawa, Takuya Miyano, Takaharu Okada, Mark van Logtestijn, Reiko J Tanaka, Atsushi Miyawaki, Masayuki Amagai
4: Maturation of Human iPSC-Derived Cardiac Microfiber with Electrical Stimulation Device.
Adv Healthc Mater .
Akari Masuda, Yuta Kurashina, Hidenori Tani, Yusuke Soma, Jumpei Muramatsu, Shun Itai, Shugo Tohyama, Hiroaki Onoe