||Kazu Kobayakawa, Yasuyuki Ohkawa, Shingo Yoshizaki, Tetsuya Tamaru, Takeyuki Saito, Ken Kijima, Kazuya Yokota, Masamitsu Hara, Kensuke Kubota, Yoshihiro Matsumoto, Katsumi Harimaya, Keiko Ozato, Takahiro Masuda, Makoto Tsuda, Tomohiko Tamura, Kazuhide Inoue, V Reggie Edgerton, Yukihide Iwamoto, Yasuharu Nakashima, Seiji Okada, Macrophage centripetal migration drives spontaneous healing process after spinal cord injury., Science advances, 10.1126/sciadv.aav5086, 5, 5, eaav5086, 2019.05, Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury..
||Kazu Kobayakawa, Kyleigh Alexis DePetro, Hui Zhong, Bau Pham, Masamitsu Hara, Akihito Harada, Jumpei Nogami, Yasuyuki Ohkawa, V Reggie Edgerton, Locomotor Training Increases Synaptic Structure With High NGL-2 Expression After Spinal Cord Hemisection., Neurorehabilitation and neural repair, 10.1177/1545968319829456, 33, 3, 225-231, 2019.03, BACKGROUND: We previously demonstrated that step training leads to reorganization of neuronal networks in the lumbar spinal cord of rodents after a hemisection (HX) injury and step training, including increases excitability of spinally evoked potentials in hindlimb motor neurons. METHODS: In this study, we investigated changes in RNA expression and synapse number using RNA-Seq and immunohistochemistry of the lumbar spinal cord 23 days after a mid-thoracic HX in rats with and without post-HX step training. RESULTS: Gene Ontology (GO) term clustering demonstrated that expression levels of 36 synapse-related genes were increased in trained compared with nontrained rats. Many synaptic genes were upregulated in trained rats, but Lrrc4 (coding NGL-2) was the most highly expressed in the lumbar spinal cord caudal to the HX lesion. Trained rats also had a higher number of NGL-2/synaptophysin synaptic puncta in the lumbar ventral horn. CONCLUSIONS: Our findings demonstrate clear activity-dependent regulation of synapse-related gene expression post-HX. This effect is consistent with the concept that activity-dependent phenomena can provide a mechanistic drive for epigenetic neuronal group selection in the shaping of the reorganization of synaptic networks to learn the locomotion task being trained after spinal cord injury..
||Masamitsu Hara, Kazu Kobayakawa, Yasuyuki Ohkawa, Hiromi Kumamaru, Kazuya Yokota, Takeyuki Saito, Ken Kijima, Shingo Yoshizaki, Katsumi Harimaya, Yasuharu Nakashima, Seiji Okada, Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin–N-cadherin pathway after spinal cord injury, Nature Medicine, 10.1038/nm.4354, 23, 7, 818-828, 2017.06.
||Kazu Kobayakawa, Hiromi Kumamaru, Hirokazu Saiwai, Kensuke Kubota, Yasuyuki Ohkawa, Junji Kishimoto, Kazuya Yokota, Ryosuke Ideta, Keiichiro Shiba, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue, Yukihide Iwamoto, Seiji Okada, Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans, SCIENCE TRANSLATIONAL MEDICINE, 10.1126/scitranslmed.3009430, 6, 256, 256ra137 1, 2014.10, Spinal cord injury (SCI) is a devastating disorder for which the identification of exacerbating factors is urgently needed. We demonstrate that transient hyperglycemia during acute SCI is a detrimental factor that impairs functional improvement in mice and human patients after acute SCI. Under hyperglycemic conditions, both in vivo and in vitro, inflammation was enhanced through promotion of the nuclear translocation of the nuclear factor kappa B (NF-kappa B) transcription factor in microglial cells. During acute SCI, hyperglycemic mice exhibited progressive neural damage, with more severe motor deficits than those observed in normoglycemic mice. Consistent with the animal study findings, a Pearson chi(2) analysis of data for 528 patients with SCI indicated that hyperglycemia on admission (glucose concentration >= 126 mg/dl) was a significant risk predictor of poor functional outcome. Moreover, a multiple linear regression analysis showed hyperglycemia at admission to be a powerful independent risk factor for a poor motor outcome, even after excluding patients with diabetes mellitus with chronic hyperglycemia (regression coefficient, -1.37; 95% confidence interval, -2.65 to -0.10; P < 0.05). Manipulating blood glucose during acute SCI in hyperglycemic mice rescued the exacerbation of pathophysiology and improved motor functional outcomes. Our findings suggest that hyperglycemia during acute SCI may be a useful prognostic factor with a negative impact on motor function, highlighting the importance of achieving tight glycemic control after central nervous system injury..
||Hiromi Kumamaru, Yasuyuki Ohkawa, Hirokazu Saiwai, Hisakata Yamada, Kensuke Kubota, Kazu Kobayakawa, Koichi Akashi, Hideyuki Okano, Yukihide Iwamoto, Seiji Okada, Seiji Okada, Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells, Nature Communications, 10.1038/ncomms2132, 3, 1140-1140, 2012.11, Neural stem/progenitor cell (NSPC) transplantation is a promising treatment for various neurodegenerative disorders including spinal cord injury, however, no direct analysis has ever been performed on their in vivo profile after transplantation. Here we combined bioimaging, flow-cytometric isolation and ultra-high-throughput RNA sequencing to evaluate the cellular properties of engrafted NSPCs. The acutely transplanted NSPCs had beneficial effects on spinal cord injury, particularly neuroprotection and neurohumoral secretion, whereas their in situ secretory activity differed significantly from that predicted in vitro. The RNA-sequencing of engrafted NSPCs revealed dynamic expression/splicing changes in various genes involved in cellular functions and tumour development depending on graft environments. Notably, in the pathological environment, overall transcriptional activity, external signal transduction and neural differentiation of engrafted NSPCs were significantly suppressed. These results highlight the vulnerability of engrafted NSPCs to environmental force, while emphasizing the importance of in situ analysis in advancing the efficacy and safety of stem cell-based therapies. © 2012 Macmillan Publishers Limited. All rights reserved..