Updated on 2023/03/14

写真a

 
FURUHASHI Kazuhiro
 
Organization
Nagoya University Hospital Nephrology Lecturer of hospital
Title
Lecturer of hospital

Degree 1

  1. 医学博士 ( 2013.5   名古屋大学 ) 

Research Interests 5

  1. 腎臓

  2. 再生医療

  3. 腎臓

  4. 再生医療

  5. 免疫学

Research Areas 3

  1. Life Science / Nephrology  / Nephrology

  2. Life Science / Nephrology  / Nephrology

  3. Life Science / Immunology

Current Research Project and SDGs 2

  1. 再生医療

  2. 腎臓内科

Research History 10

  1. Nagoya University   Nagoya University Hospital Nephrology   Lecturer of hospital

    2021.6

  2. Nagoya University   Nagoya University Hospital Nephrology   Assistant Professor

    2020.4 - 2021.5

  3. Nagoya University   Nagoya University Hospital Department of Blood Purification   Assistant professor of hospital

    2019.4 - 2020.3

  4. Nagoya University   Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division   Designated assistant professor

    2018.8 - 2019.3

  5. Columbia University   Columbia Center for Translational Immunology   Research Scientist

    2015.9 - 2018.7

  6. Harvard Medical School and Brigham and Women's Hospital   Pathology   Postdoc

    2014.1 - 2015.8

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    Country:United States

  7. 名古屋大学大学院医学系研究科   腎臓内科

    2008.4 - 2014.1

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    Country:Japan

  8. 中津川市民病院   腎臓内科

    2007.4 - 2008.3

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    Country:Japan

  9. 春日井市民病院   腎臓内科

    2003.4 - 2007.3

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    Country:Japan

  10. 春日井市民病院   研修医

    2001.5 - 2003.3

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    Country:Japan

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Education 1

  1. Nagoya University   Faculty of Medicine

    1995.4 - 2001.3

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    Country: Japan

Professional Memberships 6

  1. The Japanese Society of Internal Medicine

  2. The Japanese Society of Internal Medicine

  3. The Japanese Society for Dialysis Therapy

  4. Japanese Society of Nephrology

  5. The Japanese Society of Inflammation and Regeneration

  6. American Society of Nephrology

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Awards 6

  1. 進行性腎炎におけるTNFR1,TNFR2の役割

    2013   アステラス病態代謝研究会  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  2. 脂肪由来間葉系幹細胞を用いた壊死性半月体形成性腎炎への新たな治療法の確立とその作用機序の解明

    2011   第3回腎疾患と高血圧研究会  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  3. 急速進行性糸球体腎炎における免疫調整性(M2)マクロファージの役割― マクロファージに関するパラダイムシフト

    2010   愛知腎臓財団  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  4. 脂肪由来間葉系幹細胞(ASC)を用いた難治性腎疾患・自己免疫疾患への新たな治療開発

    2010   分子腎臓フォーラム  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  5. New Strategy for autoimmune disease and nephritis MSCs have immunoregulatory properties

    2009   愛知腎臓財団  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  6. 慢性腎臓疾患に対する新規再生医療の開発

    2007   那古野医学振興会研究奨励金  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

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Papers 29

  1. Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2.

    Mysore V, Tahir S, Furuhashi K, Arora J, Rosetti F, Cullere X, Yazbeck P, Sekulic M, Lemieux ME, Raychaudhuri S, Horwitz BH, Mayadas TN

    The Journal of experimental medicine   Vol. 219 ( 5 )   2022.5

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    DOI: 10.1084/jem.20210562

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  2. Photoactivatable Cre recombinase 3.0 for in vivo mouse applications. International journal

    Morikawa K, Furuhashi K, de Sena-Tomas C, Garcia-Garcia AL, Bekdash R, Klein AD, Gallerani N, Yamamoto HE, Park SE, Collins GS, Kawano F, Sato M, Lin CS, Targoff KL, Au E, Salling MC, Yazawa M

    Nature communications   Vol. 11 ( 1 ) page: 2141 - 2141   2020.5

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    Optogenetic genome engineering tools enable spatiotemporal control of gene expression and provide new insight into biological function. Here, we report the new version of genetically encoded photoactivatable (PA) Cre recombinase, PA-Cre 3.0. To improve PA-Cre technology, we compare light-dimerization tools and optimize for mammalian expression using a CAG promoter, Magnets, and 2A self-cleaving peptide. To prevent background recombination caused by the high sequence similarity in the dimerization domains, we modify the codons for mouse gene targeting and viral production. Overall, these modifications significantly reduce dark leak activity and improve blue-light induction developing our new version, PA-Cre 3.0. As a resource, we have generated and validated AAV-PA-Cre 3.0 as well as two mouse lines that can conditionally express PA-Cre 3.0. Together these new tools will facilitate further biological and biomedical research.

    DOI: 10.1038/s41467-020-16030-0

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  3. Generation of functional lungs via conditional blastocyst complementation using pluripotent stem cells.

    Mori M, Furuhashi K, Danielsson JA, Hirata Y, Kakiuchi M, Lin CS, Ohta M, Riccio P, Takahashi Y, Xu X, Emala CW, Lu C, Nakauchi H, Cardoso WV

    Nature medicine   Vol. 25 ( 11 ) page: 1691 - 1698   2019.11

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    DOI: 10.1038/s41591-019-0635-8

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  4. CD150<sup>high</sup> Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine. Reviewed

    Hirata Y, Furuhashi K, Ishii H, Li HW, Pinho S, Ding L, Robson SC, Frenette PS, Fujisaki J

    Cell stem cell   Vol. 22 ( 3 ) page: 445 - 453.e5   2018.3

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    DOI: 10.1016/j.stem.2018.01.017

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  5. Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life.

    Senda T, Dogra P, Granot T, Furuhashi K, Snyder ME, Carpenter DJ, Szabo PA, Thapa P, Miron M, Farber DL

    Mucosal immunology   Vol. 12 ( 2 ) page: 378 - 389   2019.3

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    DOI: 10.1038/s41385-018-0110-8

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  6. Neutrophil Fc gamma RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases Reviewed

    Hiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark J. Miller, Yunfeng Chen, Florencia Rosetti, Samantha L. Hamilton, Lihua Yang, Spencer P. Pittman, Jiexi Liao, Jan M. Herter, Jeffrey C. Berry, Daniel J. DeAngelo, Cheng Zhu, George C. Tsokos, Tanya N. Mayadas

    JOURNAL OF CLINICAL INVESTIGATION   Vol. 127 ( 10 ) page: 3810 - 3826   2017.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC CLINICAL INVESTIGATION INC  

    The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc gamma RIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc gamma RIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc gamma RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc gamma RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc gamma RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.

    DOI: 10.1172/JCI94039

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  7. Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase International journal

    Hayasaki Takahiro, Ishimoto Takuji, Doke Tomohito, Hirayama Akiyoshi, Soga Tomoyoshi, Furuhashi Kazuhiro, Kato Noritoshi, Kosugi Tomoki, Tsuboi Naotake, Lanaspa Miguel A, Johnson Richard J, Maruyama Shoichi, Kadomatsu Kenji

    JOURNAL OF NUTRITIONAL BIOCHEMISTRY   Vol. 71   page: 54 - 62   2019.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.

    DOI: 10.1016/j.jnutbio.2019.05.017

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  8. Serum-Starved Adipose-Derived Stromal Cells Ameliorate Crescentic GN by Promoting Immunoregulatory Macrophages Reviewed

    Furuhashi K, Tsuboi N, Shimizu A, Katsuno T, Kim H, Saka Y, Ozaki T, Sado Y, Imai E, Matsuo S, Maruyama S.

    Journal of the American Society of nephrology   Vol. 24   page: 587-603   2013.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1681

  9. Adipose derived stromal cells cultured in a low serum medium, but not bone marrow derived stromal cells, impede xenoantibody production. Reviewed

    5. Saka Y, Furuhashi K, Katsuno T, Kim H, Ozaki T, Iwasaki K, Haneda M, Sato W, Tsuboi N, Ito Y, Matsuo S, Kobayashi T, Maruyama S.

    Xenotransplantation   Vol. 18   page: 196-208   2011.6

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    DOI: 10.1111

  10. Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network. International journal

    Yuko Shimamura, Kazuhiro Furuhashi, Akihito Tanaka, Munetoshi Karasawa, Tomoya Nozaki, Shintaro Komatsu, Kenshi Watanabe, Asuka Shimizu, Shun Minatoguchi, Makoto Matsuyama, Yuriko Sawa, Naotake Tsuboi, Takuji Ishimoto, Hiroshi I Suzuki, Shoichi Maruyama

    Communications biology   Vol. 5 ( 1 ) page: 753 - 753   2022.7

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    Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

    DOI: 10.1038/s42003-022-03712-2

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  11. Long non-coding RNA lnc-CHAF1B-3 promotes renal interstitial fibrosis by regulating EMT-related genes in renal proximal tubular cells.

    Imai K, Ishimoto T, Doke T, Tsuboi T, Watanabe Y, Katsushima K, Suzuki M, Oishi H, Furuhashi K, Ito Y, Kondo Y, Maruyama S

    Molecular therapy. Nucleic acids   Vol. 31   page: 139 - 150   2023.3

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    Renal interstitial fibrosis (RIF) is a common pathological manifestation of chronic kidney diseases. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is considered a major cause of RIF. Although long non-coding RNAs (lncRNAs) are reportedly involved in various pathophysiological processes, the roles and underlying molecular mechanisms of lncRNAs in the progression of RIF are poorly understood. In this study, we investigated the function of lncRNAs in RIF. Microarray assays showed that expression of the lncRNA lnc-CHAF1B-3 (also called claudin 14 antisense RNA 1) was significantly upregulated in human renal proximal tubular cells by both transforming growth factor-β1 (TGF-β1) and hypoxic stimulation, accompanied with increased expression of EMT-related genes. Knockdown of lnc-CHAF1B-3 significantly suppressed TGF-β1-induced upregulated expression of collagen type I alpha 1, cadherin-2, plasminogen activator inhibitor-1, snail family transcriptional repressor I (SNAI1) and SNAI2. Quantitative reverse transcriptase PCR analyses of paraffin-embedded kidney biopsy samples from IgA nephropathy patients revealed lnc-CHAF1B-3 expression was correlated positively with urinary protein levels and correlated negatively with estimated glomerular filtration rate. In situ hybridization demonstrated that lnc-CHAF1B-3 is expressed only in proximal tubules. These findings suggest lnc-CHAF1B-3 affects the progression of RIF by regulating EMT-related signaling. Thus, lnc-CHAF1B-3 is a potential target in the treatment of RIF.

    DOI: 10.1016/j.omtn.2022.12.011

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  12. Assessment of Antibody-Titer Changes after Second and Third Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccination in Japanese Post-Kidney-Transplant Patients

    Fujieda Kumiko, Tanaka Akihito, Kikuchi Ryosuke, Takai Nami, Saito Shoji, Yasuda Yoshinari, Fujita Takashi, Kato Masashi, Furuhashi Kazuhiro, Maruyama Shoichi

    VACCINES   Vol. 11 ( 1 )   2023.1

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    Post-renal-transplant patients have a relatively low antibody-acquisition rate following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. In this study, antibody titers were measured 5–6 months and 3 weeks to 3 months after the second and third SARS-CoV-2 mRNA vaccinations, respectively. Post-renal-transplant patients visiting our hospital who had received three SARS-CoV-2 mRNA vaccine doses were included in the study. SARS-CoV-2 immunoglobulin G antibody titers were measured three times: between 3 weeks and 3 months after the second vaccination, 5–6 months after the second vaccination, and between 3 weeks and 3 months after the third vaccination. A total of 62 (40 men and 22 women) were included, 44 of whom (71.0%) were antibody positive after their third vaccination. On comparing the antibody-acquired and antibody-non-acquired groups, body mass index (BMI, odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.07–1.93, p < 0.05) and the estimated glomerular filtration rate (eGFR, OR: 1.14, 95% CI: 1.06–1.24, p < 0.01) were associated with antibody acquisition. Therefore, in Japanese post-kidney-transplant patients, increases in the antibody-acquisition rate and absolute antibody titer after the third vaccination were observed, with BMI and eGFR associated with the antibody-acquisition rate.

    DOI: 10.3390/vaccines11010134

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  13. Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

    Kitai Hiroki, Kato Noritoshi, Ogami Koichi, Komatsu Shintaro, Watanabe Yu, Yoshino Seiko, Koshi Eri, Tsubota Shoma, Funahashi Yoshio, Maeda Takahiro, Furuhashi Kazuhiro, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Kadomatsu Kenji, Suzuki Hiroshi I

    BMC BIOLOGY   Vol. 20 ( 1 ) page: 248   2022.11

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    Background: Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression (“neighborhood” miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. Results: Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites (“seed overlap” miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, “seed overlap” miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive “seed overlap” is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes—those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both “seed overlap” and “neighborhood” miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. Conclusions: Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

    DOI: 10.1186/s12915-022-01447-4

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  14. Influence of COVID-19 on the 10-year carbon footprint of the Nagoya University Hospital and medical research centre

    Morooka Hikaru, Yamamoto Takanori, Tanaka Akihito, Furuhashi Kazuhiro, Miyagawa Yasuhiro, Maruyama Shoichi

    GLOBALIZATION AND HEALTH   Vol. 18 ( 1 ) page: 92   2022.11

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    Background:: Amidst the climate crisis, a key goal of the medical sector is to reduce its large carbon footprint. Although the Coronavirus disease 2019 (COVID-19) pandemic greatly impacted the medical sector, its influence on carbon footprints remains unknown. Therefore, the aim of this study was to evaluate changes in the carbon footprint of a university hospital with a medical research centre over the past 10 years. Methods:: Data on electricity, gas, and water usage, pharmaceutical and medical supply costs, and waste amounts were recorded for Nagoya University Hospital from April 2010 to March 2021. The relevant emission factors were obtained from the Japanese government and the overall monthly carbon footprint was reported according to the Greenhouse Gas Protocol. The effect of the COVID-19 pandemic on the carbon footprint was then compared for three types of emission sources. Moreover, a regression model was used to plot quadratic functions as approximate functions using monthly carbon emissions and monthly average external temperatures. Finally, the monthly carbon footprint was calculated per hospital admission. Results:: The overall carbon footprint of the hospital was 73,546 tCO2e in 2020, revealing an increase of 26.60% over the last 10 years. Carbon emissions from electricity consumption represented 26% of total emissions. The individual carbon footprints of pharmaceuticals, medical supplies, waste, and water usage also increased from 2010 to 2020. The overall monthly carbon footprint was positively correlated with the average monthly temperature (R2 = 0.7566, p < 0.001). Compared with 2019, the overall carbon footprint decreased by 2.19% in 2020. Moreover, the monthly carbon footprint per hospital admission increased significantly between 2018 (0.24 tCO2e/admission) and 2020 (0.26 tCO2e/admission) (p = 0.002). Conclusion:: The overall carbon footprint of the hospital generally increased over the last decade. During the COVID-19 epidemic in 2020, the carbon footprint decreased slightly, likely because of the reduced number of patients. However, the carbon footprint per admission increased, which was attributed to more complicated patient backgrounds because of the ageing population. Therefore, evaluation of carbon emissions in the medical sector is urgently required in order to act on the climate crisis as soon as possible.

    DOI: 10.1186/s12992-022-00883-9

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  15. Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease and Sleep Apnea Syndrome

    Watanabe Yu, Tanaka Akihito, Furuhashi Kazuhiro, Saito Shoji, Maruyama Shoichi

    FRONTIERS IN MEDICINE   Vol. 9   page: 899359   2022.5

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    Background: The incidence of sleep apnea syndrome (SAS) is reported to be markedly high in patients with chronic kidney disease (CKD). Therefore, it is extremely important to know whether SAS affects prognosis in patients with CKD. Further, it is imperative to understand the prognostic impact of home continuous positive airway pressure (CPAP) therapy, which is one of the most common treatments for SAS. Materials and Methods: We used a clinical database to identify patients with CKD using diagnosis codes. We included patients with CKD aged 20 years or more, not on renal replacement therapy, with a known change in renal function for at least 1 year. The propensity score was used to compare event rates for patients with SAS and those without SAS. In addition, the prognostic impact of CPAP therapy was investigated. The primary outcome is a composite of death, initiation of renal replacement therapy, hospitalization for heart failure, ischemic heart disease, and cerebrovascular disease. Results: From the database, 31,294 patients with CKD without SAS and 1,026 with SAS were found to be eligible. Of these, 419 (41%) patients with SAS and 10,713 (34%) patients without SAS (P < 0.01) reached the primary outcome. After adjustment with the propensity score, the SAS group was found to have a similarly poor prognosis (P < 0.01): the hazard ratio for the primary outcome was 1.26 (95% CI, 1.08–1.45, P < 0.01) in the group with SAS compared with the group without SAS. Conversely, in patients with SAS and using CPAP, the hazard ratio was lower and did not differ significantly (HR 0.96, 95% CI: 0.76–1.22, P = 0.76). Conclusion: In patients with CKD and SAS, the risk of death and cardiovascular disease is high. In addition, patients treated with CPAP may have improved life expectancy.

    DOI: 10.3389/fmed.2022.899359

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  16. Protocol for a Phase 1, Open-Label, Multiple-Center, Dose-Escalation Study to Evaluate the Safety and Tolerability of ADR-001 in the Treatment of Immunoglobulin A Nephropathy. International journal

    Akihito Tanaka, Kazuhiro Furuhashi, Kumiko Fujieda, Kayaho Maeda, Shoji Saito, Tetsushi Mimura, Yosuke Saka, Tomohiko Naruse, Takuji Ishimoto, Tomoki Kosugi, Fumie Kinoshita, Yachiyo Kuwatsuka, Shinobu Shimizu, Yasuhiro Nakai, Shoichi Maruyama

    Frontiers in medicine   Vol. 9   page: 883168 - 883168   2022.5

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    Introduction: Immunoglobulin A (IgA) nephropathy is a disease that presents with urinary symptoms such as glomerular hematuria and urinary protein positivity, with predominant deposition of IgA in the mesangial region of the glomerulus. Corticosteroids are mainly used for treatment; however, infection is a serious adverse event, and evidence regarding therapeutic efficacy is insufficient, thus new treatments are strongly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function in inflammatory environments by converting the character of leukocytes from inflammatory to anti-inflammatory and inducing the proliferation and differentiation of organ component cells, respectively. These properties of MSCs have led to their clinical application in various inflammatory diseases, but this study is the first clinical trial of MSCs for refractory glomerulonephritis in the world. This study is registered and assigned the number, jRCT2043200002 and NCT04342325. Methods: This will be a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. ADR-001 will be administered intravenously to from three to six patients at a dose of 1 × 108 cells once in the first cohort and to six patients twice at 2-week intervals in the second cohort, and observation will continue until 52 weeks. The primary endpoint will be the evaluation of adverse events up to 6 weeks after the start of ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events, clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate. Results: Following the administration of ADR-001 to patients with IgA nephropathy, the respective percentages of patients with adverse events, asymptomatic pulmonary emboli, clinical remission, partial remission, urine protein remission, hematuria remission, their time to remission, changes in urine protein, hematuria, and glomerular filtration rate will be determined. Conclusion: This study will evaluate the safety and tolerability of ADR-001 and confirm its therapeutic efficacy in adult patients with refractory IgA nephropathy.

    DOI: 10.3389/fmed.2022.883168

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  17. Monocytes transition to monocyte‐macrophages within the inflamed vasculature via CCR2 on monocytes and endothelial TNFR2 Invited Reviewed

    Vijayashree Sathyanarayana Mysore, Suhail Tahir, Kazuhiro Furuhashi, Jatin Arora, Florencia Rosetti, Xavier Cullere, Pascal Yazbeck, Miroslav Sekulic, Madeleine E Lemieux, Soumya Raychaudhuri, Bruce Horwitz, Tanya Mayadas

      Vol. 36   2022.5

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    DOI: doi.org/10.1096/fasebj.2022.36.S1.R3229

  18. Antibody response to double SARS-CoV-2 mRNA vaccination in Japanese kidney transplant recipients

    Fujieda Kumiko, Tanaka Akihito, Kikuchi Ryosuke, Takai Nami, Saito Shoji, Yasuda Yoshinari, Fujita Takashi, Kato Masashi, Furuhashi Kazuhiro, Maruyama Shoichi

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 6850   2022.4

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    Immunocompromised patients, especially those who undergo kidney transplantation, have lower antibody levels following SARS-CoV-2 mRNA vaccination. The situation of transplant treatment, such as transplant source and immunosuppressive drugs, is different in Japan than that in other countries. Therefore, it is necessary to clarify whether antibody acquisition rates differ between Japan and other countries. This retrospective study included patients with post-kidney transplant who were attending at the Nagoya University Hospital. The anti-SARS-CoV-2 IgG antibody titers were measured between 3 weeks and 3 months after vaccination. Seventy-three patients (45 men and 28 women) were included. Of these, 23 (31.5%) showed antibody presence, and the rates of antibody acquisition were very low than those in the control group (100.0% vs. 31.5%, P < 0.05). Antibody acquisition rates were associated with body mass index (odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04–1.39, P < 0.05) and the duration between transplantation and vaccination (OR: 1.01, 95% CI: 1.00–1.02, P < 0.05). The immunosuppressive drugs used were: prednisolone in all cases, tacrolimus in 89.0%, cyclosporine in 9.6%, and mofetil mycophenolate in 97.3%. None of the patients were excluded from receiving two doses of the vaccine due to adverse effects. The study indicated that vaccination-induced antibody acquisition rates against SARS-CoV-2 were extremely low in Japanese patients who underwent post-kidney transplantation. Thus, despite two doses of vaccination, it is necessary to closely monitor infection control in such patients.

    DOI: 10.1038/s41598-022-10510-7

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  19. A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts

    Shun Minatoguchi, Shoji Saito, Kazuhiro Furuhashi, Yuriko Sawa, Masaki Okazaki, Yuko Shimamura, Ahmad Baseer Kaihan, Yusaku Hashimoto, Yoshinari Yasuda, Akitoshi Hara, Yasuyuki Mizutani, Ryota Ando, Noritoshi Kato, Takuji Ishimoto, Naotake Tsuboi, Nobutoshi Esaki, Makoto Matsuyama, Yukihiro Shiraki, Hiroki Kobayashi, Naoya Asai, Atsushi Enomoto, Shoichi Maruyama

    Scientific Reports   Vol. 12 ( 1 ) page: 5389   2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Perivascular mesenchymal cells (PMCs), which include pericytes, give rise to myofibroblasts that contribute to chronic kidney disease progression. Several PMC markers have been identified; however, PMC heterogeneity and functions are not fully understood. Here, we describe a novel subset of renal PMCs that express Meflin, a glycosylphosphatidylinositol-anchored protein that was recently identified as a marker of fibroblasts essential for cardiac tissue repair. Tracing the lineage of Meflin<sup>+</sup> PMCs, which are found in perivascular and periglomerular areas and exhibit renin-producing potential, showed that they detach from the vasculature and proliferate under disease conditions. Although the contribution of Meflin<sup>+</sup> PMCs to conventional α-SMA<sup>+</sup> myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin<sup>+</sup> PMCs in a renal fibrosis mouse model revealed their essential role in collagen production. Consistent with this, human biopsy samples showed that progressive renal diseases exhibit high Meflin expression. Furthermore, Meflin overexpression in kidney fibroblasts promoted bone morphogenetic protein 7 signals and suppressed myofibroblastic differentiation, implicating the roles of Meflin in suppressing tissue fibrosis. These findings demonstrate that Meflin marks a PMC subset that is functionally distinct from classic pericytes and myofibroblasts, highlighting the importance of elucidating PMC heterogeneity.

    DOI: 10.1038/s41598-022-09331-5

    Web of Science

    Scopus

    PubMed

  20. 腎移植レシピエントにおけるSARS-CoV-2 mRNAワクチン接種後の抗体獲得率

    安田 宜成, 田中 章仁, 菊地 良介, 高井 奈美, 齋藤 尚二, 藤田 高史, 加藤 真史, 古橋 和拡, 丸山 彰一

    移植   Vol. 57 ( Supplement ) page: s270_3 - s270_3   2022

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    Language:Japanese   Publisher:一般社団法人 日本移植学会  

    <p>【背景】腎移植レシピエントでは免疫抑制療法のためSARS-CoV-2 mRNA vaccinat</p><p>ionによる抗体獲得率が低いと報告されている。本邦では諸外国と比較し、生体腎移植が多く、免疫抑制薬の治療レジメなどが異なる。日本人腎移植レシピエントのワクチン接種後の交代獲得率を調査した。</p><p>【方法】対象は名古屋大学医学部付属病院へ通院中の日本人腎移植レシピエントのうち、SARS-CoV-2 mRNAワクチンを受けて、抗体価を測定した106名。抗体価は2回のワクチン接種後3週間から3か月の間にSARS-CoV-2 IgG II Quant Reagent Kit(R)により測定し、50 AU/mL以上を陽性とした。</p><p>【結果】対象者106名中で陽性は41名(38.6%)であった。抗体獲得率に関連する因子として、BMI(OR 1.24, 95% CI 1.08-1.41, P<0.05)、移植からの期間(OR 1.01, 95% CI 1.00-1.02, P<0.05)、eGFR(OR 1.07, 95% CI 1.02-1.11, P<0.05)が関連した。</p><p>【結論】腎移植レシピエントはSARS-CoV-2 mRNAワクチン接種後の抗体獲得率が低く、ワクチン接種後も厳重な感染対策を継続しなければならない。加えて免疫抑制治療中の患者において抗体獲得率を高めるSARS-CoV-2 mRNAワクチン接種方法の検討が必要である。</p>

    DOI: 10.11386/jst.57.supplement_s270_3

    CiNii Research

  21. Acute kidney injury and cytokines

    Furuhashi K

    Acute Kidney Injury and Regenerative Medicine     page: 333 - 351   2020.1

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    Language:Japanese   Publisher:Acute Kidney Injury and Regenerative Medicine  

    Cytokines and chemokines are potential signaling molecules that maintain homeostasis by activating intracellular communication. Cytokines orchestrate various processes, ranging from cellular survival, proliferation, and chemotaxis for tissue repair to regulation of inflammation. Extracellular vesicles (EVs), which are cell-derived membrane particles such as exosomes and microvesicles, may also play crucial roles similar to cytokines. The kidneys are highly susceptible to intrinsic oxidative stress resulting from ischemia and to the excessive inflammatory response resulting from systemic autoimmunity. These types of stress may eventually result in the development of acute kidney injury (AKI). In this setting, the skewed cytokine profile produced by macrophages and lymphocytes disrupts the reciprocal relationship for regulating tissue repair and remodeling due to amplification of a physiological vicious loop. We have so far shown that AKI induces the secretion of midkine (MK) and CD147/basigin, which are responsible for skewed cytokine production. MK and CD147/basigin secreted by tubular epithelial cells promote the recruitment of macrophages and neutrophils, respectively, which are accompanied by monocyte chemotactic protein- 1, transforming growth factor-β, E cadherin, and extracellular matrix metalloproteinase inducer. This chapter will present the functions of macrophage-related cytokines and EVs and summarize our findings on how MK and CD147/basigin are involved in the pathogenesis of AKI.

    DOI: 10.1007/978-981-15-1108-0_23

    Scopus

  22. Therapeutic Application of Adipose Derived Mesenchymal Stem Cells for Kidney Diseases

    Furuhashi Kazuhiro, Maruyama Shoichi

    Nihon Naika Gakkai Zasshi   Vol. 109 ( 4 ) page: 812 - 818   2020

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    Language:Japanese   Publisher:The Japanese Society of Internal Medicine  

    DOI: 10.2169/naika.109.812

    CiNii Research

  23. Adenosine from Niche-Associated Tregs Maintains Hematopoietic Stem Cell Quiescence Reviewed

    Hirata Y, Furuhashi K, Ishi H, Li H, Pinho S,Ding L, Frenette P, Fujisaki J.

    Blood   ( 130 ) page: 91   2017.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: https://doi.org/10.1182/blood.V130.Suppl_1.91.91

  24. Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis Reviewed

    Endo N, Tsuboi N, Furuhashi K, Shi Y, Du Q, Abe T, Hori M, Imaizumi T, Kim H, Katsuno T, Ozaki T, Kosugi T, Matsuo S,Maruyama S.

    Nephrology Dialysis Transplantation   Vol. 31   page: 2023-2033   2016.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1093

  25. Transfusion of CD206+ M2 Macrophages Ameliorates Antibody Mediated Glomerulonephritis in Mice Reviewed

    Du Q, Tsuboi N, Shi Y, Ito S, Sugiyama Y, Furuhashi K, Endo N, Kim H, Katsuno T, Akiyama S, Matsuo S, Isobe K, Maruyama S.

    The American Journal of Pathology   Vol. 186   page: 3176-3188   2016.8

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    Language:English   Publishing type:Research paper (scientific journal)  

  26. Midkine Regulates BP through Cytochrome P450 Derived Eicosanoids Reviewed

    Sato Y, Sato W, Maruyama S, Wilcox C, Falck J, Masuda T, Kosugi T, Kojima H, Maeda K, Furuhashi K, Ando M, Imai E, Matsuo S, Kadomatsu K.

    Journal of the American Society of nephrology   Vol. 26   page: 1806-1815   2015.8

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    Language:English   Publishing type:Research paper (scientific journal)  

  27. Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency Reviewed

    Shi Y, Tsuboi N, Furuhashi K, Du Q, Horinouchi A, Maeda K, Kosugi T, Matsuo S, Maruyama S.

    The Journal of Immunology     page: 5129-5139   2014.11

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.4049

  28. Rat adipose tissue derived stem cells attenuate peritoneal injuries in rat zymosan induced peritonitis accompanied by complement activation Reviewed

    Kim H, Mizuno M, Furuhashi K, Katsuno T, Ozaki T, Yasuda K, Tsuboi N, Sato W, Suzuki Y, Matsuo S, Ito Y, Maruyama S.

    Cytotherapy   Vol. 16   page: 357-368   2013.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016

  29. Low Serum Cultured Adipose Tissue-Derived Stromal Cells Ameliorate Acute Kidney Injury in Rats Reviewed

    Katsuno T, Ozaki T, Saka Y, Furuhashi K, Kim H, Yasuda K, Yamamoto T, Sato W, Tsuboi N, Mizuno M, Ito Y, Imai E, Matsuo S, Maruyama S.

    Cell transplantation   Vol. 22   page: 287-297   2013.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3727

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Books 7

  1. 脂肪由来幹細胞を用いた腎炎の治療

    田中章仁( Role: Joint author)

    医学のあゆみ・医歯薬出版  2020.10 

  2. 間葉系幹細胞を用いた腎疾患治療法の開発

    古橋和拡・田中章仁・唐澤宗稔・丸山彰一( Role: Joint author)

    科学評論社  2020.8 

  3. Acute Kidney Injury and Cytokines

    ( Role: Joint author)

    Acute Kidney Injury and Regenerative Medicine  2020.5 

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    Total pages:p333-351   Language:English

  4. Acute Kidney Injury and Cytokines

    ( Role: Joint author)

    Acute Kidney Injury and Regenerative Medicine  2020.5 

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    Total pages:p333-351   Language:English

  5. 脂肪由来間葉系幹細胞を用いた腎疾患治療

    古橋和拡, 丸山彰一( Role: Joint author)

    日本内科学会雑誌  2020.4 

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    Language:Japanese

  6. 脂肪由来間葉系幹細胞を用いた腎疾患治療

    古橋和拡・丸山彰一( Role: Joint author)

    日本内科学会雑誌  2020.4 

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    Language:Japanese

  7. Annual Review 腎臓

    古橋和拡、丸山彰一、坪井直毅( Role: Joint author)

    中外医学社  2012.1 

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    Language:Japanese Book type:Scholarly book

    脂肪由来間葉系幹細胞(ASC)を用いた難治性腎疾患・自己免疫疾患への新たな治療開発

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MISC 2

  1. CD150<sup>high</sup> Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine. Reviewed

    Hirata Y, Furuhashi K, Ishii H, Li HW, Pinho S, Ding L, Robson SC, Frenette PS, Fujisaki J

    Cell stem cell   Vol. 22 ( 3 ) page: 445 - 453.e5   2018.3

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

    DOI: 10.1016/j.stem.2018.01.017

    PubMed

  2. Neutrophil Fc gamma RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases Reviewed

    Hiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark J. Miller, Yunfeng Chen, Florencia Rosetti, Samantha L. Hamilton, Lihua Yang, Spencer P. Pittman, Jiexi Liao, Jan M. Herter, Jeffrey C. Berry, Daniel J. DeAngelo, Cheng Zhu, George C. Tsokos, Tanya N. Mayadas

    JOURNAL OF CLINICAL INVESTIGATION   Vol. 127 ( 10 ) page: 3810 - 3826   2017.10

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)   Publisher:AMER SOC CLINICAL INVESTIGATION INC  

    The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc gamma RIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc gamma RIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc gamma RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc gamma RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc gamma RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.

    DOI: 10.1172/JCI94039

    Web of Science

    PubMed

Presentations 8

  1. Elucidation of therapeutic mechanism of adipose-derived mesenchymal stem cells against glomerulonephritis model by focusing on in vivo cell dynamics Invited

    Kazuhiro Furuhashi

    2021.12.3 

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    Event date: 2021.12

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  2. 脂肪間葉系幹細胞を用いた腎炎治療の可能性 〜治療特性とその作用機序〜 Invited

    古橋和拡

    再生医療学会  2021.3.13 

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    Event date: 2021.3

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  3. MESENCHYMAL STEM CELLS EXERT RENOPROTECTION VIA EXTRACELLULAR VESICLE- MEDIATED MODULATION OF M2 MACROPHAGES AND SPLEEN-KIDNEY NETWORK International conference

    Kazuhiro Furuhashi

    The International Society for Stem Cell Research (ISSCR)   2021.10.28  The International Society for Stem Cell Research (ISSCR)

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    Event date: 2021.10

    Language:English   Presentation type:Poster presentation  

    Venue:Tokyo   Country:Japan  

  4. Serum-starved adipose-derived stromal cells ameliorate rat crescentic glomerulonephritis by promoting immunoregulatory macrophages International conference

    Kazuhiro Furuhashi, Naotake Tsuboi, Asuka Shimizu, Yiqin Shi, Hangsoo Kim, Takayuki Katsuno, Yosuke Saka, Takenori Ozaki, Waichi Sato, Enyu Imai, Seiichi Matsuo, Shoichi Maruyama

    The Asia Pacifific Meeting of Vasculitis and ANCA Workshop 2012 5th International Conference on Autoimmunity: Mechanisms and Novel Treatments International Society for Stem Cell Research 10th Annual Meeting International Society for Stem Cell Research 11th Annual Meeting 

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    Event date: 2013.12

    Language:English   Presentation type:Poster presentation  

    Country:United States  

  5. 脂肪由来間葉系幹細胞を用いた壊死性半月体形成性腎炎への新たな治療法の確立とその作用機序の解明

    古橋 和拡,坪井 直毅,清水明日花,勝野 敬之,金  恒秀,松尾 清一,丸山 彰一

    第33回日本炎症・再生医学会 

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    Event date: 2012.7

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Country:Japan  

  6. LOW SERUM CULTURED ADIPOSE-DERIVED MESENCHYMAL STEM CELLS AMELIORATE CRESCENTIC GLOMERULONEPHRITIS BY FUNCTIONAL POLARIZATION OF MACROPHAGES INTO IMMUNOREGULATORY M2 PHENOTYPE International conference

    Furuhashi, Kazuhiro, Tsuboi, Naotake, Shimizu, Asuka, Kim, Hangsoo, Katsuno, Takayuki, Saka, Yosuke, Maruyama, Shoichi

    International Society for Stem Cell Research 10th Annual Meeting 

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    Event date: 2012.6

    Language:English   Presentation type:Poster presentation  

    Country:Greece  

  7. Low Serum Cultured Adipose-derived Mesenchymal Stem Cells Ameliorate Crescentic Glomerulonephritis by Functional Polarization of Macrophages into Immunoregulatory M2 Phenotype International conference

    Kazuhiro Furuhashi, Naotake Tsuboi, Asuka Shimizu, Yiqin Shi, Hangsoo Kim, Takayuki Katsuno, Yosuke Saka, Takenori Ozaki, Waichi Sato, Enyu Imai, Seiichi Matsuo, Shoichi Maruyama

    The Asia Pacifific Meeting of Vasculitis and ANCA Workshop 2012 

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    Event date: 2012.3

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  8. Low serum cultured adipose-derived mesenchymal stromal cells, but not bone-marrow derived mesenchymal stem cells, ameliorate rat crescentic glomerulonephritis by functional polarization of macrophages into immunoregulatory M2 phenotype International conference

    Kazuhiro Furuhashi, Naotake Tsuboi, Seiichi Matsuo, and Shoichi Maruyama

    5th International Conference on Autoimmunity: Mechanisms and Novel Treatments 

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    Event date: 2011.9

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

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Research Project for Joint Research, Competitive Funding, etc. 2

  1. 生体がもつ巧妙な炎症制御機構の解明から治療応用へ

    2021.4 - 2028.3

    国立研究開発法人科学技術振興機構(JST)  創発的研究支援事業 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

  2. 間葉系幹細胞治療用中空糸膜カラムの開発

    2021.4 - 2024.3

    AMED: 国立研究開発法人日本医療研究開発機構  再生医療実現拠点ネットワークプログラム(技術開発個別課題) 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

KAKENHI (Grants-in-Aid for Scientific Research) 14

  1. 生体がもつ巧妙な炎症制御機構の解明から治療応用へ

    2021.4 - 2028.3

    国立研究開発法人科学技術振興機構(JST)  創発的研究支援事業 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

  2. 間葉系幹細胞治療用中空糸膜カラムの開発

    2021.4 - 2024.3

    AMED: 国立研究開発法人日本医療研究開発機構  再生医療実現拠点ネットワークプログラム(技術開発個別課題) 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

  3. 糸球体周囲マクロファージは基底膜を貫く樹状突起によりポドサイト恒常性を維持する

    Grant number:22K19523  2022.6 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    古橋 和拡, 丸山 彰一, 田中 章仁

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    Authorship:Principal investigator 

    Grant amount:\6370000 ( Direct Cost: \4900000 、 Indirect Cost:\1470000 )

    本研究では、通常の組織学的観察で見出せず、最新のイメージング技術である生体顕微鏡・臓器透明化を用いることで初めて観察することができたマクロファージのユニークな構造と細胞間networkに関して、その生物学的意味を解明する。独自に開発した生体顕微鏡技術・組織固定技術・組織透明化技術を融合することで、本課題の科学的問いは初めて解決することができるため、独自性の高い挑戦的な研究である。本課題は組織幹細胞niche研究に細胞形態学・細胞動態学を取り入れた新たな研究フィールドを創生し、細胞形態に関わる蛋白を治療ターゲットとした新たな治療法へと発展させ、ポドサイト再生に関わる因子の同定することを目指す。

  4. 間葉系幹細胞カラムとiPS細胞・遺伝子編集技術を融合した新規治療システム

    Grant number:22H03087  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(B)

    古橋 和拡, 高須 正規, 平山 明由, 鈴木 洋, 丸山 彰一, 田中 章仁, 森 崇

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    これまでの間葉系幹細胞(MSC)研究を通して、臨床応用時の問題点の解決と治療特性に関わる作用機序について解明を進めてきた。循環動態が悪い際の経静脈的な細胞投与は細胞塞栓の危険があり、この問題を解決するために、新たな治療装置としてMSCカラムの開発を進めている。さらに、細胞ソースの問題を解決するため、iPS細胞からMSCを作成する研究を進めている。
    本課題では、iPS細胞、MSCカラム、解明した治療機序を融合した新規治療システムを開発し、将来的に遺伝編集技術・細胞治療が新たに創生する治療フィールドを見据えた基盤技術へと発展させる。

  5. aHUS早期診断及び抗補体薬の適応判断に必要な補体機能検査開発

    Grant number:22K08349  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    加藤 規利, 前田 佳哉輔, 丸山 彰一, 水野 正司, 古橋 和拡, 小杉 智規

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    Authorship:Coinvestigator(s) 

    aHUSは血液中ではなく、血管内皮細胞膜上での無秩序な補体活性化が問題であり、単純な採血で評価できないところに検査開発の難しさがある。我々は、2020年より開始したaHUS全国調査研究で登録のあった症例の血漿から、細胞外小胞(Exosomes)を精製し、Exosomes上の補体関連タンパクを測定し、細胞膜上の補体活性を評価する。またex vivoでaHUS患者の血漿と血管内皮細胞株との反応系にエクリズマブを添加することにより、実際に薬剤を投与する前に、治療反応性を見極める。

  6. 塩基性ヘリックスループヘリックス転写機構制御と細胞治療を融合する神経再生治療開発

    Grant number:22K09280  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    西村 由介, 永島 吉孝, 夏目 敦至, 古橋 和拡

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    Authorship:Coinvestigator(s) 

    申請者らは『損傷脊髄を完全に再生する驚異的な能力を持つアフリカツメガエル幼生期に強く発現し、脊髄再生に関わるNeurod4などの塩基性ヘリックスループヘリックス(bHLH)神経転写因子を歯髄幹細胞に遺伝子導入してラット脊髄損傷モデルに投与することで、歯髄幹細胞自体をニューロンへ分化させ神経回路を再構築し、神経栄養因子分泌による脊髄再生効果に相加的かつ加速度的な神経機能回復が得られる』という仮説を立て、これを実証する。

  7. 間葉系幹細胞の微小環境での炎症制御機構に着眼した次世代型免疫・炎症制御法の創成

    Grant number:21H04824  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(A)

    丸山 彰一, 石本 卓嗣, 平山 明由, 榎本 篤, 秋山 真一, 田中 章仁, 杉浦 悠毅, 古橋 和拡

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    既存の免疫抑制薬は過剰免疫抑制による感染症などの副作用が問題となっている。間葉系幹細胞(MSC)は、障害部位の炎症強度に応じた自律的かつ局所での炎症制御が可能なことから、次世代の免疫制御療法として期待されている。しかし、その作用機序は十分解明されておらず、その実用化に際しては課題が多い。新概念として『障害部位に到達したMSC由来細胞外小胞が炎症細胞から放出される炎症性物質と微小空間で会合した時にのみ免疫抑制物質が生成されて局所での抗炎症作用が出現する』という着想に至った。本研究では、この新概念を検証して、効果的で安全な次世代型免疫・炎症制御療法の開発に取り組む。

  8. フルクトース代謝を標的とした糖尿病性腎臓病の病態解明と新規治療法の開発

    Grant number:21K08254  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    石本 卓嗣, 小杉 智規, 古橋 和拡, 平山 明由

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    これまでに、グルコースより内因性に産生される過剰なフルクトース代謝が糖尿病性腎臓病(DKD)およびメタボリック症候群・脂肪肝を進展させることを報告し、フルクトース代謝酵素KHK-Cを抑制する治療法の開発に取り組んできた。本研究は、①腎尿細管のKHK-C依存的フルクトース代謝の抑制によるDKDの進展抑制効果およびその機序を解明し、②高い酵素耐性を持つ非環状型人工核酸を用いたKHK-Cを阻害する核酸医薬を開発する。
    1) KHK-C依存的フルクトース代謝の抑制による、異常解糖系の改善・DKDの進展抑制効果を解明する。
    CRISPR-Cas9システムにより作成したKHK-Cのみを欠損するKHK-C KOマウスおよびKHK-A KOマウス、KHK-A/C KOマウス、野生型マウスを用い、2ヶ月令時にストレプトゾトシン誘導性の糖尿病モデルを作成した。ストレプトゾトシン投与半年後に腎障害の評価を行う予定である。また、KHK-Cを強制発現した不死化近位尿細管細胞HK-2にフルクトース・グルコース刺激を行い、過剰なフルクトース代謝の解糖系(ECAR)・ミトコンドリア呼吸(OCR)への影響を、細胞外フラックスアナライザーにより解析している。
    2)KHK-Cを選択的に阻害する核酸医薬および低分子化合物を作成し、DKDおよびMS・脂肪肝に対する新規治療法を開発する。
    KHK-Cを選択的に阻害するsiRNAを作成し、KHK-Cのノックダウン効率およびKHK-Aへの影響を含めたオフターゲット効果を評価した。同様の配列を用い、KHK-Cを選択的に阻害するアンチセンスオリゴヌクレオチドを作成した。マウスへの投与による評価を開始している。
    KHK-Cノックアウトマウスを含めた複数のノックアウトマウス(KHK-C KO、KHK-A KO、KHK-A/C KO)のコロニーを拡大し、野生型マウス含めてストレプトゾトシン誘導性の糖尿病モデルをすでに作成しており、現在、評価時期の検討しつつ経過をみている。また、フラックスアナライザーによる実験評価系も安定しつつあり、評価を進めている。また、KHK-Cを選択的に阻害する核酸については、siRNAは有用な配列が同定できている。アンチセンスオリゴヌクレオチドについても概ね有効性を確認しているが、さらなる抑制効率の向上のために検討を進めている。
    1)KHK-C依存的フルクトース代謝の抑制による、異常解糖系の改善・DKDの進展抑制効果を解明する。
    ストレプトゾトシン誘導性の糖尿病モデルについて、随時、蛋白尿や尿細管障害マーカーを測定し、野生型マウスにおける腎障害モデルの疾患重症度を確認しつつ屠殺時期を最終決定し、解析する。培養細胞を用いたフラックスアナライザーによる検討も引き続き進める。
    <BR>
    2)KHK-Cを選択的に阻害する核酸医薬および低分子化合物を作成し、DKDおよびMS・脂肪肝に対する新規治療法を開発する。
    KHK-Cを選択的に阻害する核酸について、アンチセンスオリゴヌクレオチドによるよく成功率を更に高められる配列・塩基長・核酸修飾について検討を続ける。マウスへの核酸の全身投与については、アンチセンスオリゴヌクレオチドの皮下投与など、投与経路を含めた評価を行い、腎・肝におけるKHK-C選択的阻害効果を検討する。

  9. ヒトiPS細胞由来間葉系幹細胞を用いた新規腎疾患治療法の開発

    Grant number:21K08253  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    田中 章仁, 石本 卓嗣, 丸山 彰一, 古橋 和拡

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    間葉系幹細胞(MSC)は様々な疾患に対する治療効果が示されている。しかし、MSCは品質のばらつきがあるため、治療効果の担保が大きな問題となっている。本課題では、iPS細胞からMSCを分化誘導し、腎炎に対する治療効果が安定して高いことを確認し、MSCの欠点を克服する。さらに治療効果を高める操作を加え、これまでのMSCよりも、腎炎に対して各段に高い治療効果を得る。最終的には、既存の治療法を凌駕する、難治性腎疾患に対する全く新しい細胞治療を確立する。
    ヒト人工多能性幹細胞(iPS細胞)から、既報を参考に、間葉系幹細胞(MSC)の誘導を行った。誘導した細胞は細胞の形態、表面マーカーなどもMSCとして矛盾ない結果であった。この誘導は比較的安定した再現性をもって、施行可能であった。もともと当教室ではMSC、特に低血清培養脂肪由来MSC(LASC)の研究が精力的に行われており、LASC研究での実績を参考にして、実験に用いるモデル動物の作成を行った。さらにそのモデル動物に対して、MSC投与の条件検討を行い、誘導したMSCが最も高い治療効果を発揮する投与プロトコルや、治療効果を評価するプロトコルの確立も行った。さらに、継代数がどこまで進んでも問題ないのか、あるいはどの継代数のものを用いるのが適切か、などの検討も進めている。
    最終的には、複数のiPS細胞株からMSCを誘導し、モデルマウスやモデルラットへの細胞投与実験を進めている。まだ様々な細胞株での実験中であり、明確かつ安定した治療効果を結論付けるには至っていないが、腎疾患に対するMSCの有効性を示唆する結果が見られつつある。また、LASCとの、あるいは骨髄由来のMSCとの、腎疾患に対する有効性の比較実験も進めている。
    また、誘導したMSCの治療効果に関する機序の解明についても、実験を進めている。誘導したMSCが分泌する、Growth factorなどの検討も行っている。
    研究の今後の発展を見据えて、大型モデル動物の作成を進めている。大型モデル動物への治療効果を踏まえ、最終的にはヒトへの応用を進めていくことを計画している。
    明確かつ安定した治療効果を結論付けるには至っていないが、iPS細胞から誘導したMSCの、腎疾患に対する有効性を示唆する結果は得られつつある。今後は再現性を確認しつつ、当教室の有するLASCとの比較、さらに機序解析などを進めて行く状況であるため。
    今後はiPS細胞から誘導したMSCの、腎疾患に対する有効性について、再現性を確認していく。当教室の有するLASCと、腎疾患に対する有効性の比較を進める。さらに機序解析などを進めていく。その上で、iPS細胞を用いることの有用性について、検討していく。

  10. 特異的な間葉系幹細胞マーカーMeflinを介した腎線維化の機序解明と治療法の開発

    Grant number:20K08589  2020.4 - 2023.3

    科学研究費助成事業  基盤研究(C)

    齋藤 尚二, 丸山 彰一, 古橋 和拡, 榎本 篤

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    1)Meflinの正常腎ならびに疾患モデルマウスにおける発現を正常マウスならびにMeflinノックアウトマウスを用いて解析する
    2)Meflin陽性細胞の腎線維化に関する役割をMeflin-CreERT2;Rosa26-LSL-tdtomatoマウスを用いて経時的・空間的に系譜追跡し解明する
    3)Meflin-ZsGreen-DTR-Creマウスを用いてMeflin陽性細胞を消去し、その役割を解明する
    4)Meflinの発現を誘導することにより、腎線維化進展や臓器不全の予防につながる治療法を開発する
    当初の予定として、以下を計画していた。
    1)Meflinの正常腎ならびに疾患モデルマウスにおける発現を正常マウスならびにMeflinノックアウトマウスを用いて解析する。
    2)Meflin陽性細胞の腎線維化に関する役割をMeflin-CreERT2;Rosa26-LSL-tdtomatoマウスを用いて経時的・空間的に系譜追跡し解明する。
    3)Meflin-ZsGreen-DTR-Creマウスを用いてMeflin陽性細胞を消去し、その役割を解明する。
    4)Meflinの発現を誘導することにより、腎線維化進展や臓器不全の予防につながる治療法を開発する。
    これらの計画のうち、主に1)、2)、3)について主に実験が進んでいる。腎臓におけるMeflinの発現の検討により、正常腎においてはMeflinが腎間質の他にも糸球体門部や一部血管壁に分布していることを確認した。上記の遺伝子改変マウスを用いて解析を進めたところ、改めてMeflin陽性細胞が間質ならびに糸球体門部やその近辺の血管壁な局在することが確認できた。このマウスに腎線維化を誘導したところ、線維化マウスにMeflin陽性細胞が増えることも確認できた。これらの解析の結果も踏まえて、Meflin陽性細胞が腎線維化をきたす血管周囲の間葉系幹細胞の有用なマーカーとなり得ることを見出した。この研究成果はScienticif Reports誌に論文を掲載することができた。
    当初より計画していた実験計画の内、Meflinノックアウトマウス、Meflin-CreERT2;Rosa26-LSL-tdtomatoマウス、Meflin-ZsGreen-DTR-Creマウスを用いた解析が順調に進んでいる。
    <BR>
    これらの解析の結果も踏まえて、Meflin陽性細胞が腎線維化をきたす血管周囲の間葉系幹細胞の有用なマーカーとなり得ることを見出した。この研究成果はScienticif Reports誌に論文を掲載することができた。
    当初の予定通り、引き続き以下のマウスの表現型の解析を行っていく。
    1)Meflinの正常腎ならびに疾患モデルマウスにおける発現を正常マウスならびにMeflinノックアウトマウスを用いて解析する。2)Meflin陽性細胞の腎線維化に
    関する役割をMeflin-CreERT2;Rosa26-LSL-tdtomatoマウスを用いて経時的・空間的に系譜追跡し解明する。3)Meflin-ZsGreen-DTR-Creマウスを用いてMeflin陽性細胞を消去し、その役割を解明する。4)Meflinの発現を誘導することにより、腎線維化進展や臓器不全の予防につながる治療法を開発する。
    また4)のようにMeflinを誘導する手法を検索している。最終的には腎線維化進展や臓器不全の予防につながる治療法を開発することが目的である。

  11. Screening of humoral pathogenesis of idiopathic focal segmental glomerulosclerosis by proteinuria visualized transparent model animal

    Grant number:19K22618  2019.6 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

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  12. Novel CaMK4-mediated podocyte-specific therapy in refractory renal disease

    Grant number:19K08723  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Maeda Kayaho

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    We elucidated the role of CaMK4 in refractory nephrotic syndrome such as focal segmental glomerulosclerosis, and developed podocyte-specific therapy. The findings using podocyte-specific CaMK4-deficient mice showed that CaMK4 in podocytes is involved in podocyte cell death and induces more proteinuria, and podocyte-directed nanoparticles with a CaMK4 inhibitor showed the efficacy compared to administration without nanoparticles.

  13. Development of new cell therapy columns to solve current problems in mesenchymal stem cell therapy

    Grant number:19K08722  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Furuhashi Kazuhiro

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    In the clinical application of mesenchymal stem cells (MSCs), pulmonary embolism is a serious side effect when MSCs are administered intravenously. To solve this problem, we are developing an MSC therapeutic hollow fiber membrane column (MSC column) in which only liquid factors secreted from MSCs are administered into the body without directly injecting cells into the body. We have selected the optimal material for MSCs packed outside the hollow fiber membrane in the column. Furthermore, the cells in the created MSC columns were able to secrete many growth factors, leading to the MSC columns ameliorating the rat nephritis model.

  14. Development of a treatment for septic AKI using microRNAs and adipose stem cell-derived exosomes.

    Grant number:19K08676  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Noritoshi Kato

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    In our previous studies, we have succeeded in suppressing hypercytokinemia and improving survival in sepsis model mice by systemic administration of a plasmid expressing miR-146a, which was mainly taken up by the spleen.
    In this study, we focused on the spleen as a target for the treatment of sepsis and investigated the therapeutic effect of local injection into the spleen. We found that most of the nucleic acids after administration were taken up by the spleen, especially by splenic macrophages. While the therapeutic effect was protective against organ damage such as kidney and liver damage, this did not improve the survival rate. Therefore, the target disease and therapeutic miRNAs were changed, and the inhibitory effect on renal fibrosis caused by folic acid nephropathy was examined, and a certain inhibitory effect on fibrosis was confirmed.

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Industrial property rights 5

  1. 間葉系幹細胞の培養方法

    古橋和拡 丸山彰一 田中章仁 高須正規 春原隆司 山口悟

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    Applicant:国立大学法人東海国立大学機構・ニプロ株式会社

    Application no:特願2022-054023  Date applied:2022.3

    Date published:2023

  2. 腎臓中のCD25陽性の制御性T細胞増加剤

    東海国立大学機構,ロート製薬

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    Date applied:2021.4

    Announcement no:WO2021/210515  Date announced:2021.10

    Country of applicant:Foreign country   Country of acquisition:Foreign country

  3. 尿細管間質障害の検出用バイオマーカー並びにその用途

    古橋和拡, 丸山彰一, 田中章仁, 澤由里子, LSIメディエンス

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    Application no:特願2021-108341  Date applied:2021

  4. 脂肪由来間葉系幹細胞ADR-001による腎疾患治療法の開発

    古橋和拡

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    Application no:特願2020- 71737  Date applied:2020.4

    Rights holder:古橋和拡・丸山彰一・田中章仁・唐澤宗稔・ロート株式会社

  5. IMMUNOSUPPRESSING AGENT COMPRISING MESENCHYMAL STEM CELL DERIVED FROM ADIPOSE TISSUE, AND USE THEREOF

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    Application no:PCT/JP2010/064682  Date applied:2010.8

    Date announced:2011.4

    Country of applicant:Domestic  

 

Teaching Experience (On-campus) 2

  1. 腎臓内科

    2021

  2. 腎臓内科

    2020