1: Microenvironmental modulation in tandem with human stem cell transplantation enhances functional recovery after chronic complete spinal cord injury
Science of the Month - March 2023
Biomaterials.
2023 Jan 26;295:122002. doi: 10.1016
Shogo Hashimoto, Narihito Nagoshi, Munehisa Shinozaki, Katsuyuki Nakanishi, Yu Suematsu, Takahiro Shibata, Momotaro Kawai 4, Takahiro Kitagawa 4, Kentaro Ago, Yasuhiro Kamata, Kaori Yasutake, Ikuko Koya, Yoshinari Ando, Aki Minoda, Tomoko Shindo, Shinsuke Shibata, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano
For chronic complete spinal cord injury, which accounts for the majority of spinal cord injury patients, there are no effective treatments even in animal experiments. We have been exploring the development of combination therapies using stem cell transplantation with other treatments. Cell transplantation monotherapy has poor engraftment rates for transplanted cells due to various nerve regeneration inhibitors, resulting in limited functional improvement. Therefore, a key therapeutic strategy is to alter the spinal cord microenvironment before transplantation to enhance the effectiveness of the transplanted cells.
In this study, we successfully restored hindlimb motor function in a rat model of chronic complete injury by transplanting human iPS-derived neural stem/progenitor cells after implanting a sustained-release scaffold containing hepatocyte growth factor. By first implanting the scaffold, we improved the spinal cord environment and created a substrate for regeneration. Subsequent cell transplantation improved the engraftment rate of the transplanted cells, and the formation of new neural circuits led to improved hindlimb motor function. This is a significant study that could become an effective treatment for chronic complete spinal cord injury.
(Shogo Hashimoto, Class of '93, Department of Orthopedic Surgery; Class of '62, Department of Physiology; Narihito Nagoshi, Class of '81, Department of Orthopedic Surgery)
2: Subarachnoid hemorrhage triggers neuroinflammation of the entire cerebral cortex, leading to neuronal cell death
Inflamm Regen.
Yamada H, Kase Y*, Okano Y, Kim D, Goto M, Takahashi S, Okano H**, Toda M**
* senior author ** corresponding author
This paper reveals that in the early stages of subarachnoid hemorrhage, neuroinflammation spreads throughout the entire cerebral cortex, causing neuronal cell death and leading to severe outcomes. Subarachnoid hemorrhage remains a disease with a high mortality rate, and no effective treatment has been established for the early-stage neural damage it causes.
The authors created mouse models of subarachnoid hemorrhage with varying severity and discovered that 24 hours after induction, neuroinflammation and neuronal cell death occurred not only near the lesion but also in the distal cerebral cortex. While the importance of early-stage damage in subarachnoid hemorrhage has been noted, it was not previously known that neuroinflammation is not confined to the vicinity of the hemorrhage but spreads throughout the entire brain, causing neuronal cell death.
These findings suggest that suppressing inflammation throughout the cerebral cortex during the acute phase after subarachnoid hemorrhage is effective for neuroprotection. The research group has begun to investigate how suppressing neuroinflammation can be developed into an effective treatment.
(Hiroki Yamada, Class of '94, and Masahiro Toda, Class of '66, Department of Neurosurgery; Yoshitaka Kase, equivalent to Class of '91, and Hideyuki Okano, Class of '52, Department of Physiology)
3: IDH2 stabilizes HIF-1a-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer
EMBO J.
2023 Feb 15;42(4):e110620. doi: 10.15252
Keisuke Shigeta, Masanori Hasegawa*, Takako Hishiki, Yoshiko Naito, Yuto Baba, ShujiMikami, Kazuhiro Matsumoto, Ryuichi Mizuno, AkiraMiyajima, Eiji Kikuchi, Hideyuki Saya, Takeo Kosaka** & Mototsugu Oya***
Urothelial carcinoma (UC) that has become resistant to anticancer drugs is one of the most intractable urological cancers. This study is the first report to discover the metabolic network regulatory mechanism in urothelial carcinoma after the acquisition of resistance to chemotherapy (Gemcitabine/Cisplatin). Using the metabolomics core facility at our university, comprehensive metabolome analysis revealed that drug-resistant strains undergo metabolic reprogramming. Specifically, enhanced glutamine metabolism drives the TCA cycle in reverse, leading to the accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). This accumulation suppresses the degradation of Hif-1α and activates the anaerobic glycolysis pathway even under 20% oxygen. We found that this results in pharmacological antagonism to anticancer drugs and enhanced antioxidant effects against reactive oxygen species. This series of metabolic reprogramming mechanisms is controlled by isocitrate dehydrogenase 2 (IDH2), which has recently gained attention as a metabolic checkpoint molecule. We found that controlling or inhibiting the function of IDH2 significantly improves the therapeutic effect of anticancer drugs. These results are expected to have a ripple effect, improving chemosensitivity in UC patients.
(Takeo Kosaka, equivalent to Class of '79, Department of Urology)
Other Published Papers
1: Loss of epigenetic information as a cause of mammalian aging
Cell.
2023 Jan 19;186(2):305-326.e27. doi: 10.1016
Jae-Hyun Yang, Motoshi Hayano, Patrick T Griffin, João A Amorim, Michael S Bonkowski, John K Apostolides, Elias L Salfati, Marco Blanchette, …Andreas R Pfenning, Luis A Rajman, David A Sinclair
2: Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex.
Nature Communications.
Tabata H, Sasaki M, Agetsuma M, Sano H, Hirota Y, Miyajima M, Hayashi K, Honda T, Nishikawa M
3: Changes in telepsychiatry regulations during the COVID-19 pandemic: 17 countries and regions' approaches to an evolving healthcare landscape.
Psychological Medicine.
Kinoshita S, Cortright K, Crawford A, Mizuno Y, Yoshida K, Hilty D, Guinart D, Torous J, Correll CU, Castle DJ, Rocha D, Yang Y, Xiang YT, Kolbaek P, Dines D, ElShami M, Jain P, Kallivayalil R, Solmi M, Favaro A, Veronese N, Seedat S, Shin S, de Pablo GS, Chang CH, Su KP, Karas H, Kane JM, Yellowlees P, Kishimoto T.
4: Early postoperative non-steroidal anti-inflammatory drugs and anastomotic leakage after oesophagectomy.
British Journal of Surgery.
Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y.
5: Mod(mdg4) variants repress telomeric retrotransposon HeT-A by blocking subtelomeric enhancers.
Nucleic Acids Research.
Takeuchi C, Yokoshi M, Kondo S, Shibuya A, Saito K, Fukaya T, Siomi H, Iwasaki YW.