Shuhei Ito

Keio University

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Myelopathy due to Spinal Extramedullary Hematopoiesis in a Patient with Polycythemia Vera

Case Reports in Orthopedics (2017)

Shuhei Ito Nobuyuki Fujita Naobumi Hosogane Narihito Nagoshi Mitsuru Yagi

Extramedullary hematopoiesis (EMH) occasionally occurs in patients exhibiting hematological disorders with decreased hematopoietic efficacy. EMH is rarely observed in the spinal epidural space and patients are usually asymptomatic. In particular, in the patients with polycythemia vera, spinal cord compression due to EMH is extremely rare. We report a case of polycythemia vera, in which operative therapy proved to be an effective treatment for myelopathy caused by spinal EMH.

Extramedullary hematopoiesis

Spinal cord compression

Spinal Cord Diseases

Bone Marrow Diseases

10.1155/2017/2416365

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Citations (7)

Development of DNA microarray system : From Bench to Bed in Esophageal Cancers

Cytometry research : 日本サイトメトリー学会機関誌 (2002)

Takefumi Ohga Shinji Tanaka Shin‐ichiro Maehara Motonori Futatsugi Shuhei Ito

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Administration of C5a Receptor Antagonist Improves the Efficacy of Human Induced Pluripotent Stem Cell–Derived Neural Stem/Progenitor Cell Transplantation in the Acute Phase of Spinal Cord Injury

Journal of Neurotrauma (2022)

Reo Shibata Narihito Nagoshi Keita Kajikawa Shuhei Ito Shinsuke Shibata

Human-induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation during the acute phase of spinal cord injury (SCI) is not effective due to the inflammatory response occurring immediately after SCI, which negatively impacts transplanted cell survival. Therefore, we chose to study the powerful chemoattractant complement C5a as a method to generate a more favorable transplantation environment. We hypothesized that suppression of the inflammatory response immediately after SCI by C5a receptor antagonist (C5aRA) would improve the efficacy of hiPSC-NS/PCs transplantation for acute phase SCI. Here, we evaluated the influence of C5aRA on the inflammatory reaction during the acute phase after SCI, and observed significant reductions in several inflammatory cytokines, macrophages, neutrophils, and apoptotic markers. Next, we divided the SCI mice into four groups: 1) phosphate-buffered saline (PBS) only; 2) C5aRA only; 3) PBS + transplantation (PBS+TP); and 4) C5aRA + transplantation (C5aRA+TP). Immediately after SCI, C5aRA or PBS was injected once a day for 4 consecutive days, followed by hiPSC-NS/PC transplantation or PBS into the lesion epicenter on Day 4. The C5aRA+TP group had better functional improvement compared with the PBS only group. The C5aRA+TP group also had a significantly higher cell survival rate compared with the PBS+TP group. This study demonstrates that administration of C5aRA can suppress the inflammatory response during the acute phase of SCI, while improving the survival rate of transplanted hiPSC-NS/PCs, as well as enhancing motor functional restoration. Human-induced pluripotent stem cell-derived neural stem/progenitor cell transplantation with C5aRA is a promising treatment during the acute injury phase for SCI patients.

10.1089/neu.2021.0225

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Promoter hypermethylation and quantitative expression analysis of CDKN2A (p14ARF and p16INK4a) gene in esophageal squamous cell carcinoma.

PubMed (2007)

Shuhei Ito Takefumi Ohga Hiroshi Saeki Masayuki Watanabe Yoshihiro Kakeji

Abnormal hypermethylation of the CDKN2A (p14ARF and p16INK4a) gene can lead to repression of gene expression and contribute to carcinogenesis and tumor progression.In esophageal squamous cell carcinoma (ESCC), the promoter methylation of the p14ARF and p16INK4a gene was investigated in 38 cases by methylation-specific PCR and the expression of each gene in 18 cases was quantified by real-time quantitative reverse transcription-PCR.Aberrant methylation of p14ARF and of p16INK4a was detected in 23 (61%) and 29 (76%) cases, respectively. No relationship was found between clinicopathological variables and p14ARF or p161NK4a promoter methylation. A statistically significant association between p14ARF methylation status and mRNA expression was found (p=0.0441). Regarding p14ARF, a low expression group showed a significantly higher proportion of cases with deep invasion of tumor, lymph node metastasis, and a high TNM stage of disease (p=0.0474, 0.0474, and 0.0441, respectively), and a significantly poor prognosis (p=0.0402). Regarding p161NK4a, no relationship was found among the methylation status, mRNA expression and clinicopathological variables, including survival.Our results suggest that methylation is the predominant mechanism of inactivation of the p14ARF gene in ESCC. The decrease in p14ARF gene expression associated with invasive and metastatic phenotypes may be significant as an indicator of the malignant potential of human ESCC.

p14arf

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LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice

eNeuro (2018)

Shuhei Ito Narihito Nagoshi Osahiko Tsuji Shinsuke Shibata Munehisa Shinozaki

Abstract

Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. However, this report used a hemi-section model, which does not represent the majority of clinical SCI cases, and lacked a detailed histological analysis of other descending tracts. To determine the true therapeutic effects of LOTUS, we used a more clinically relevant contusive SCI model in female transgenic mice. Definitive tracing analyses revealed that LOTUS promoted the extensive regeneration of the reticulospinal tract across the lesion site and suppressed axonal dieback of corticospinal tract (CST). A significant increase in raphespinal tract fibers was seen from the subacute to the chronic phase after the injury, strongly suggesting that LOTUS promoted translesional elongation of this tract. Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.

Corticospinal tract

10.1523/eneuro.0303-18.2018

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Citations (35)

Impact of Growing Rod Surgery for Early-onset Scoliosis on Cervical Sagittal Alignment

Spine Surgery and Related Research (2024)

Shuhei Ito Satoshi Suzuki Yohei Takahashi Masahiro Ozaki Osahiko Tsuji

10.22603/ssrr.2024-0022

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Abstract 3908: The mechanism of premetastatic niche formation through FBXW7/NOTCH/CCL2 pathway and clinical trial using CCL2 inhibitor “SK-818” for breast cancer patients

Cancer Research (2017)

Miwa Noda Takaaki Masuda Naoki Hayashi Takahiro Kogawa Shinji Ohno

Abstract Background Metastasis is a major cause of death in cancer patients, & elucidation of the mechanisms is expected to provide a basis for the development of new cancer treatment. Premetastatic niche whereby tumors prepare defined organs for metastasized cells is considered to be crucial for the development of metastasis, which consists of host cells such as monocytes, macrophages, & other inflammatory cells. However, the mechanism of how tumor cells communicate with host cells to develop a premetastatic niche remains unclear. FBXW7 is the F-box protein component of an SCF-type ubiquitin ligase, in which it functions as a receptor responsible for substrate recognition followed by the degradation of the substrate. Some part of the substrates of FBXW7 regulates the recruitment of monocytes, macrophages, & other inflammatory cells. Therefore, we hypothesized that expression of FBXW7 in the host cells is a key determinant of the formation of premetastatic niches. Materials & Methods To investigate the role of FBXW7 in the formation of premetastatic niche, we developed bone marrow-specific FBXW7-deficient mice. 1. We transferred B16F10 melanoma cells or E0771 mouse breast cancer cells into the tail vein or mammary fat pad of the mice & the wild type mice to evaluate the metastatic potential to lung. 2. We examined the serum concentrations of various cytokines or chemokines in the mice before & after E0771 cells transplantation using cytokine array. 3. To examine whether the enhanced metastasis apparent in FBXW7-deficient mice is dependent on the CCL2/CCR2 pathway, we treated FBXW7-deficient mice with SK-818, a CCR2 antagonist. 4. We measured the expression of FBXW7 mRNA in peripheral blood of breast cancer patients by qRT-PCR & examined the relationship between FBXW7 mRNA expression & prognosis. Results 1. The extent of lung metastasis of B16F10 or E0771 cell was markedly enhanced in FBXW7-deficient mice. 2. FBXW7-deficient mice exhibited increased serum levels of CCL2. Moreover, accumulation of NOTCH & consequent transcriptional activation of CCL2 was observed in bone marrow-derived stromal cells of FBXW7-deficient mice. 3. Administration of SK-818 blocked the enhancement of lung metastasis in FBXW7-deficient mice. 4. In human breast cancer patients, low FBXW7 mRNA expression in peripheral blood showed high concentration of CCL2 in serum & poor prognosis. Conclusions We found that the FBXW7/NOTCH/CCL2 pathway play a key role in the regulation of cancer metastasis through the formation of premetastatic niches, & that SK-818 inhibit cancer metastasis in mice. SK-818 is currently administered clinically for the treatment of patients with hepatitis B virus infection in Japan. Based on these findings, we have been conducting Phase I clinical trial to assess the safety of SK-818 for breast cancer patients. Citation Format: Miwa Noda, Takaaki Masuda, Naoki Hayashi, Takahiro Kogawa, Shinji Ohno, Keiichi Nakayama, Yohsuke Kuroda, Hidetoshi Eguchi, Shuhei Ito, Masafumi Inomata, Koshi Mimori. The mechanism of premetastatic niche formation through FBXW7/NOTCH/CCL2 pathway and clinical trial using CCL2 inhibitor “SK-818” for breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3908. doi:10.1158/1538-7445.AM2017-3908

10.1158/1538-7445.am2017-3908

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Epigenetics of Placental Development and Function

Elsevier eBooks (2013)

Shuhei Ito Mitsuko Hirosawa Koji Hayakawa Shintaro Yagi Satoshi Tanaka

10.1016/b978-0-12-394445-0.00024-2

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Citations (1)

A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury

Stem Cells Translational Medicine (2020)

Yasuhiro Kamata Miho Isoda Tsukasa Sanosaka Reo Shibata Shuhei Ito

Cell-based therapy targeting spinal cord injury (SCI) is an attractive approach to promote functional recovery by replacing damaged tissue. We and other groups have reported the effectiveness of transplanting neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) in SCI animal models for neuronal replacement. Glial replacement is an additional approach for tissue repair; however, the lack of robust procedures to drive iPSCs into NS/PCs which can produce glial cells has hindered the development of glial cell transplantation for the restoration of neuronal functions after SCI. Here, we established a method to generate NS/PCs with gliogenic competence (gNS/PCs) optimized for clinical relevance and utilized them as a source of therapeutic NS/PCs for SCI. We could successfully generate gNS/PCs from clinically relevant hiPSCs, which efficiently produced astrocytes and oligodendrocytes in vitro. We also performed comparison between gNS/PCs and neurogenic NS/PCs based on single cell RNA-seq analysis and found that gNS/PCs were distinguished by expression of several transcription factors including HEY2 and NFIB. After gNS/PC transplantation, the graft did not exhibit tumor-like tissue formation, indicating the safety of them as a source of cell therapy. Importantly, the gNS/PCs triggered functional recovery in an SCI animal model, with remyelination of demyelinated axons and improved motor function. Given the inherent safety of gNS/PCs and favorable outcomes observed after their transplantation, cell-based medicine using the gNS/PCs-induction procedure described here together with clinically relevant iPSCs is realistic and would be beneficial for SCI patients.

10.1002/sctm.20-0269

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Citations (27)

First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol

Regenerative Therapy (2021)

Keiko Sugai Miho Sumida Tomoko Shofuda Ryo Yamaguchi Takashi Tamura

Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI.NS/PCs were prepared at a Good Manufacturing Practice-grade cell processing facility at Osaka National Hospital using a clinical-grade integration-free hiPSC line established by the iPSC Stock Project organized by the Kyoto University Center for iPS Cell Research and Application. After performing all quality checks, the long-term safety and efficacy of cells were confirmed using immunodeficient mouse models.The forthcoming clinical study uses an open-label, single-arm design. The initial follow-up period is 1 year. The primary objective is to assess the safety of hiPSC-NS/PC transplantation in patients with subacute SCI. The secondary objective is to obtain preliminary evidence of its impact on neurological function and quality-of-life outcomes. Four patients with C3/4-Th10 level, complete subacute (within 24 days post-injury) SCI will be recruited. After obtaining consent, cryopreserved cells will be thawed and prepared following a multi-step process including treatment with a γ-secretase inhibitor to promote cell differentiation. A total of 2 × 106 cells will be transplanted into the injured spinal cord parenchyma 14-28 days post-injury. Patients will also receive transient immunosuppression. This study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000035074; Japan Registry of Clinical Trials [jRCT] number, jRCTa031190228).We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides. The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned.

Immunosuppression

Tolerability

10.1016/j.reth.2021.08.005

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Citations (110)