1: Chemically defined cytokine-free expansion of human haematopoietic stem cells.

Nature.

2023, volume 615 ; 127–133 (2023)doi:10.1038

Sakurai M, Ishitsuka K, Ito R, Wilkinson AC, Kimura T, Mizutani E, Nishikii H, Sudo K, Becker HJ, Takemoto H, Sano T, Kataoka K, Takahashi S, Nakamura Y, Kent DG, Iwama A, Chiba S, Okamoto S, Nakauchi H, Yam

Hematopoietic stem cells (HSCs) have the ability to differentiate into blood cells such as red blood cells, white blood cells, and platelets. In hematopoietic stem cell transplantation, they play a crucial role in post-transplant hematopoietic and immune reconstitution. However, HSCs are very few in number, and the establishment of ex vivo expansion technology is particularly needed for umbilical cord blood transplantation. Until now, serum albumin and cytokines have been considered essential for the ex vivo maintenance of HSCs, but their expansion effect has been limited. We have now developed a novel culture technology that enables long-term ex vivo expansion of human HSCs using a medium in which albumin and cytokines are replaced with a high-molecular-weight polymer and specific compounds, respectively. This has made it possible to expand human HSCs contained in umbilical cord blood long-term and selectively. In the future, we aim to provide this culture technology as a basic research tool and pursue its clinical application to realize safer hematopoietic stem cell transplantation and resolve the shortage of donors.

(Masatoshi Sakurai, Department of Hematology, Class of '86)

Lancet Rheumatology.

2023 Apr;5(4):e215-e224.

Hiroya Tamai, Kei Ikeda, Toshiaki Miyamoto, Hiroaki Taguchi, Chang-Fu Kuo, Kichul Shin, Shintaro Hirata, Yutaka Okano, Shinji Sato, Hidekata Yasuoka, Masataka Kuwana, Tomonori Ishii, Hideto Kameda, Toshihisa Kojima, Takehiro Taninaga, Masahiko Mori, Hideaki Miyagishi, Yasunori Sato, Wen-Chan Tsai, Tsutomu Takeuchi, Yuko Kaneko, and MIRACLE study collaborators.

For the treatment of rheumatoid arthritis, it is recommended worldwide to start treatment with methotrexate (MTX) and add a TNF inhibitor or other drugs if the effect is insufficient. It is known that the efficacy of TNF inhibitors is enhanced when used in combination with continued MTX, but the required MTX dosage has not been clarified, and continuation of the same dose has generally been practiced.

The MIRACLE trial was a joint study with Eisai Co., Ltd., led by our university and conducted in Japan, South Korea, and Taiwan, in which 300 patients with early-stage rheumatoid arthritis participated. First, patients underwent 24 weeks of MTX monotherapy, and adalimumab was added if the treatment goal of remission was not achieved. At this point, they were assigned to either a group that continued the same dose of concomitant MTX or a group that reduced the dose. After 24 weeks, the remission achievement rate was 38% in the same-dose continuation group and 44% in the dose-reduction group, showing that the effect was not inferior in the reduction group. Adverse events tended to be less frequent in the dose-reduction group (20%) compared to the same-dose continuation group (35%). This study suggests that a safer treatment can be provided when initiating TNF inhibitors.

(Hiroya Tamai, Department of Rheumatology and Collagen Diseases, Class of '91)

Inflamm Regen.

2023 Apr 3;43(1):23. doi: 10.1186/s41232-023-00273-7

Emi Qian, Masahiro Uemura, Hiroya Kobayashi, Shiho Nakamura, Fumiko Ozawa, Sho Yoshimatsu, Mitsuru Ishikawa, Osamu Onodera, Satoru Morimoto, Hideyuki Oka

Inflammation and the accumulation of abnormal proteins are cited as causes of cerebral small vessel disease, such as Binswanger's disease, which causes dementia and motor symptoms due to cerebral arteriolosclerosis. However, the detailed pathogenic mechanism is unknown, and hereditary cerebral small vessel disease is being focused on as a clue to elucidating the pathology. HTRA1, the causative gene for CARASIL, an autosomal recessive hereditary cerebral small vessel disease, has recently been found to cause cerebral small vessel disease even with a heterozygous mutation. In this study, a research group including Emi Qian, a sixth-year student at the School of Medicine, Satoru Morimoto, a Project Lecturer at the School of Medicine's Department of Physiology, and Professor Hideyuki Okano, in collaboration with Niigata University, established the world's first iPS cells from a patient with cerebral small vessel disease carrying a heterozygous mutation in HTRA1. They found that HTRA1 expression was reduced compared to iPS cells derived from healthy individuals. Furthermore, they observed increased expression of NOGGIN, whose expression level increases with the activation of the TGF-β signal, suggesting a mechanism in which the HTRA1 mutation causes disinhibition of the TGF-β signal, leading to vascular lesions. These iPS cells are expected to be applied to further pathological analysis research by differentiating them into diseased cells.

(Satoru Morimoto, Department of Physiology, equivalent to Class of '89)

Circulation.

2023;147(3):223-238.

Tani H, Sadahiro T, Yamada Y, Isomi M, Yamakawa H, Fujita R, Abe Y, Akiyama T, Nakano K, Kuze Y, Seki M, Suzuki Y, Fujisawa M, Sakata-Yanagimoto M, Chiba S, Fukuda K, Ieda M.