細胞機能解析学分野

Yasuo Miura

  (三浦 康生)

Profile Information

Affiliation
Professor and Chair (Director), Fujita Health University School of Medicine/Fujita Health University Hospital/Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University/Department of Hematology and Oncology, RIRBM, Hiroshima University
Degree
MD, PhD(Kyoto University)

J-GLOBAL ID
201401024093350442
researchmap Member ID
7000009040

Recent appear in the TV media at https://www.youtube.com/watch?v=7XndsDFTfzg


Major Papers

 89
  • Rie Nakagawa, Hideaki Matsuura, Hayato Kojima, Yuko Abe, Ayuna Yamada, Hiroki Doi, Yasuo Miura
    Laboratory Medicine, Sep 22, 2024  Peer-reviewedLast author
    Abstract Background Donor-specific antibodies (DSAs) targeting human leukocyte antigens (HLAs) substantially reduce the longevity of transplanted organs. Desensitization of DSA-positive renal transplant recipients is achieved through intravenous administration of immunoglobulin (IVIg). However, the presence and detectability of anti-HLA antibodies in IVIg preparations following administration are not fully understood. We aimed to assess whether immunoglobulin preparations contain anti-HLA antibodies that can be detected as passive antibodies when administered into the body. Methods We evaluated 3 immunoglobulin preparations from different pharmaceutical companies, using anti-HLA class I and II antibody specificity tests and immunocomplex capture fluorescence analysis (ICFA). Results Direct testing for anti-HLA antibodies resulted in high background errors, particularly for Venoglobulin. Diluting Venoglobulin to physiological concentrations revealed the presence of anti-HLA class I antibodies; however, no common alleles were found between the specificity identification test and ICFA. For Glovenin and Venilon, anti-HLA class I and II antibodies were detected; however, variability was observed across different test reagent lots. Moreover, dilution of the globulin formulation revealed a prozone phenomenon. Conclusion The administration of IVIg complicates the accurate detection of anti-HLA antibodies, underscoring the need for careful interpretation of test results post-IVIg administration.
  • Yoshinobu Takakura, Rikinari Hanayama, Kazunari Akiyoshi, Shiroh Futaki, Kyoko Hida, Takanori Ichiki, Akiko Ishii-Watabe, Masahiko Kuroda, Kazushige Maki, Yasuo Miura, Yoshiaki Okada, Naohiro Seo, Toshihide Takeuchi, Teruhide Yamaguchi, Yusuke Yoshioka
    Pharmaceutical research, 41 1573-1594, Aug 7, 2024  Peer-reviewed
    Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.
  • Sumie Fujii, Yasuo Miura
    International Journal of Hematology, 120(3) 278-289, Jul 12, 2024  Peer-reviewedLast author
    Abstract Cytopenia is a well-documented complication in the treatment of hematological malignancies with lenalidomide and pomalidomide. Although prior studies have highlighted direct effects on hematopoietic cells to explain this adverse effect, the involvement of hematopoietic-supportive stroma remains less understood. This study examined the effects of lenalidomide/pomalidomide on the expansion and differentiation of human CD34+ hematopoietic stem/progenitor cells (HSPCs) in vitro, in co-culture with human bone-marrow mesenchymal stromal/stem cells (MSCs). Our findings indicate that lenalidomide/pomalidomide increases the population of immature CD34+CD38 cells while decreasing the number of mature CD34+CD38+ cells, suggesting a mechanism that inhibits early HSPC maturation. This effect persisted across myeloid, megakaryocytic, and erythroid lineages, with MSCs playing a key role in preserving immature progenitors and inhibiting their differentiation. Furthermore, in myeloid differentiation assays augmented by granulocyte-colony stimulating factor, lenalidomide/pomalidomide not only enhanced the presence of CD34+ cells with mature myeloid markers such as CD11b but also reduced the populations lacking CD34 yet positive for these markers, irrespective of MSC presence. Thus, while MSCs support the presence of these immature cell populations, they simultaneously inhibit their maturation. This finding provides novel mechanistic insights into lenalidomide- and pomalidomide-induced cytopenia, and could guide therapeutic strategies for its mitigation.
  • Yusuke Matsui, Yasuo Miura
    Cells, 13(1) 64-64, Dec 28, 2023  Peer-reviewedLast authorCorresponding author
    The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV transmission. However, despite the success of these regimens, the global HIV epidemic persists, prompting a comprehensive exploration of potential strategies for an HIV cure. Here, we offer a consolidated overview of cell-based therapies for HIV-1, focusing on CAR-T cell approaches, gene editing, and immune modulation. Persistent challenges, including CAR-T cell susceptibility to HIV infection, stability, and viral reservoir control, underscore the need for continued research. This review synthesizes current knowledge, highlighting the potential of cellular therapies to address persistent challenges in the pursuit of an HIV cure.
  • Sumie Fujii, Yasuo Miura
    Stem Cells, 40(11) 977-990, Nov 29, 2022  Peer-reviewedInvitedLast authorCorresponding author
    Abstract The development of human mesenchymal stromal/stem cell (MSC)-based therapy has focused on exploring biological nanoparticles secreted from MSCs. There is emerging evidence that the immunomodulatory and regenerative effects of MSCs can be recapitulated by extracellular vesicles released from MSCs (MSC-EVs). Off-the-shelf allogeneic human MSC products are clinically available to treat acute graft-versus-host disease (GVHD), but real-world data have revealed the limitations of these products as well as their feasibility, safety, and efficacy. MSC-EVs may have advantages over parental MSCs as drugs because of their distinguished biodistribution and importantly dose-dependent therapeutic effects. Recent research has shed light on the role of microRNAs in the mode-of-action of MSC-EVs. A group of specific microRNAs alone or in combination with membrane proteins, membrane lipids, and soluble factors present in MSC-EVs play key roles in the regulation of GVHD. In this concise review, we review the regulation of T-cell-mediated adaptive immunity and antigen-presenting cell-mediated innate immunity by MSC-EVs and the direct regenerative effects on damaged cells in association with the immunopathology of GVHD.
  • Hideaki Matsuura, Sumie Fujii, Yusuke Matsui, Yukari Sugiura, Hidehiko Akiyama, Yasuo Miura
    Annals of Hematology, 101(9) 1959-1969, Sep, 2022  Peer-reviewedLast authorCorresponding author
    SARS-CoV-2 infection has been reported to be associated with a positive direct antiglobulin test (DAT). In this study, an analysis of 40 consecutive coronavirus disease 2019 (COVID-19) cases from December 2020 to September 2021 in Japan revealed that patients of 70 years and over were predisposed to a positive DAT. DAT positivity was related to a decrease in the hemoglobin level. Anemia in DAT-positive COVID-19 patients was attributed to hemolysis, which was corroborated by high reticulocyte counts and an increase in the red blood cell distribution width. Human leukocyte antigen (HLA)-DRB1*12:01 and DRB1*12:02 were exclusively found in DAT-positive COVID-19 patients. In silico assays for the Spike protein of SARS-CoV-2 predicted several common core peptides that met the criteria for a B cell epitope and strong binding to both HLA-DRB1*12:01 and DRB1*12:02. Among these peptides, the amino acids sequence TSNFR, which is found within the S1 subunit of SARS-CoV-2 Spike protein, is shared by human blood group antigen Rhesus (Rh) CE polypeptides. In vitro analysis showed that the expression of HLA-DR in CD4+ T cells and CD8+ T cells from a DAT-positive patient was increased after pulsation with TSNFR-sequence-containing peptides. In summary, positive DAT is related to enhanced anemia and to HLA-DR12 in the Japanese population. A peptide sequence within SARS-CoV-2 Spike protein may act as an epitope for IgG binding to RBCs in DAT-positive COVID-19 patients.
  • Takahiro Matsuno, Hideaki Matsuura, Sumie Fujii, Ami Tanaka, Masahiro Satake, Tomohiro Kinoshita, Akihiro Tomita, Yusuke Matsui, Yukari Sugiura, Yasuo Miura
    Transfusion, 61(9) 2782-2787, Sep, 2021  Peer-reviewedLast authorCorresponding author
    BACKGROUND: The occurrence of transfusion-transmitted hepatitis B virus (HBV) infection has fallen dramatically due to continuous improvements in pre-transfusion laboratory testing. However, the characteristics of transfusion-transmitted HBV infection caused by individual donor nucleic acid amplification test (ID-NAT)-negative blood products are unclear. CASE PRESENTATION: A 76-year-old woman with acute myeloid leukemia was diagnosed with transfusion-transmitted HBV infection after receiving apheresis platelets derived from an ID-NAT-negative blood donation. This case was diagnosed definitively as transfusion-mediated because complete nucleotide homology of a 1556 bp region of the HBV Pol/preS1-preS2-S genes and a 23 bp region of the HBV core promoter/precore between the donor and recipient strains was confirmed by PCR-directed sequencing. The case is uncommon with respect to the unexpectedly prolonged HBV-DNA incubation period of nearly 5 months after transfusion (previously, the longest period observed since the recent implementation of ID-NAT pre-transfusion laboratory testing in Japan was 84 days). Slow-replicating HBV genotype A2 may contribute to the prolonged incubation period; also, the quantity of apheresis platelets delivered in a large volume of plasma, and/or the immune response of the recipient suffering from a hematological neoplasm, may have contributed to establishment of HBV infection in the recipient. This was supported by analysis of three previously documented cases of transfusion-transmitted HBV infection by blood products derived from ID-NAT-negative donations in Japan. CONCLUSION: Continuous monitoring of HBV infection for longer periods (>3 months) may be required after transfusion of blood components from an ID-NAT-negative HBV window donation.
  • Sumie Fujii, Yasuo Miura, Aya Fujishiro, Takero Shindo, Yutaka Shimazu, Hideyo Hirai, Hidetoshi Tahara, Akifumi Takaori-Kondo, Tatsuo Ichinohe, Taira Maekawa
    Stem Cells, 36(3) 434-445, Mar, 2018  Peer-reviewedCorresponding author
    © 2017 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press A substantial proportion of patients with acute graft-versus-host disease (aGVHD) respond to cell therapy with culture-expanded human bone marrow mesenchymal stromal/stem cells (BM-MSCs). However, the mechanisms by which these cells can ameliorate aGVHD-associated complications remain to be clarified. We show here that BM-MSC-derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM-MSCs against aGVHD. Systemic infusion of human BM-MSC-derived EVs prolonged the survival of mice with aGVHD and reduced the pathologic damage in multiple GVHD-targeted organs. In EV-treated GVHD mice, CD4+ and CD8+ T cells were suppressed. Importantly, the ratio of CD62L-CD44+ to CD62L + CD44- T cells was decreased, suggesting that BM-MSC-derived EVs suppressed the functional differentiation of T cells from a naive to an effector phenotype. BM-MSC-derived EVs also preserved CD4 + CD25 + Foxp3+ regulatory T cell populations. In a culture of CD3/CD28-stimulated human peripheral blood mononuclear cells with BM-MSC-derived EVs, CD3+ T cell activation was suppressed. However, these cells were not suppressed in cultures with EVs derived from normal human dermal fibroblasts (NHDFs). NHDF-derived EVs did not ameliorate the clinical or pathological characteristics of aGVHD in mice, suggesting an immunoregulatory function unique to BM-MSC-derived EVs. Microarray analysis of microRNAs in BM-MSC-derived EVs versus NHDF-derived EVs showed upregulation of miR-125a-3p and downregulation of cell proliferative processes, as identified by Gene Ontology enrichment analysis. Collectively, our findings provide the first evidence that amelioration of aGVHD by therapeutic infusion of BM-MSC-derived EVs is associated with the preservation of circulating naive T cells, possibly due to the unique microRNA profiles of BM-MSC-derived EVs. Stem Cells 2018;36:434–445.
  • Masaki Iwasa, Yasuo Miura, Aya Fujishiro, Sumie Fujii, Noriko Sugino, Satoshi Yoshioka, Asumi Yokota, Terutoshi Hishita, Hideyo Hirai, Akira Andoh, Tatsuo Ichinohe, Taira Maekawa
    International Journal of Hematology, 105(5) 587-597, May, 2017  Peer-reviewedCorresponding author
    The poor prognosis of adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is attributed to leukemia cells that are protected by the bone marrow (BM) microenvironment. In the present study, we explored the pharmacological targeting of mesenchymal stromal/stem cells in BM (BM-MSCs) to eliminate chemoresistant BCP-ALL cells. Human BCP-ALL cells (NALM-6 cells) that adhered to human BM-MSCs (NALM-6/Ad) were highly resistant to multiple anti-cancer drugs, and exhibited pro-survival characteristics, such as an enhanced Akt/Bcl-2 pathway and increased populations in the G0 and G2/S/M cell cycle stages. Bortezomib, a proteasome inhibitor, interfered with adhesion between BM-MSCs and NALM-6 cells and up-regulated the matricellular protein SPARC (secreted protein acidic and rich in cysteine) in BM-MSCs, thereby reducing the NALM-6/Ad population. Inhibition of SPARC expression in BM-MSCs using a small interfering RNA enhanced adhesion of NALM-6 cells. Conversely, recombinant SPARC protein interfered with adhesion of NALM-6 cells. These results suggest that SPARC disrupts adhesion between BM-MSCs and NALM-6 cells. Co-treatment with bortezomib and doxorubicin prolonged the survival of BCP-ALL xenograft mice, with a significant reduction of leukemia cells in BM. Our findings demonstrate that bortezomib contributes to the elimination of BCP-ALL cells through disruption of their adhesion to BM-MSCs, and offer a novel therapeutic strategy for BCP-ALL through targeting of BM-MSCs.
  • Chikashi Terao, Hajime Yoshifuji, Yoshihisa Yamano, Hiroto Kojima, Kimiko Yurugi, Yasuo Miura, Taira Maekawa, Hiroshi Handa, Koichiro Ohmura, Hiroh Saji, Tsuneyo Mimori, Fumihiko Matsuda
    Rheumatology, 55(9) 1686-1692, May 30, 2016  
  • Yasuo Miura
    International Journal of Hematology, 103(2) 119-121, Feb, 2016  Peer-reviewedInvitedLead authorLast authorCorresponding author
  • Yasuo Miura, Yusuke Matsui, Noriko Sugino, Yuko Nakato, Hideyo Takeda, Fumie Iwai, Nao Toyooka, Hitomi Kaneko, Mitsumasa Watanabe, Mitsuru Tsudo
    BRITISH JOURNAL OF HAEMATOLOGY, 152(2) 237-238, Jan, 2011  Peer-reviewed
  • Yasuo Miura, Zhigang Gao, Masako Miura, Byoung-Moo Seo, Wataru Sonoyama, WanJun Chen, Stan Gronthos, Li Zhang, Songtao Shi
    STEM CELLS, 24(11) 2428-2436, Nov, 2006  Peer-reviewed
    Bone marrow-derived mesenchymal stem cells (BMMSCs) are multipotent postnatal stem cells that have been used for the treatment of bone defects and graft-versus-host diseases in clinics. In this study, we found that subcutaneously transplanted human BMMSCs are capable of organizing hematopoietic progenitors of recipient origin. These hematopoietic cells expressed multiple lineages of hematopoietic cell associated markers and were able to rescue lethally irradiated mice, with successful engraftment in the recipient, suggesting a potential bone marrow (BM) resource for stem cell therapies. Furthermore, we found that platelet-derived growth factor (PDGF) promotes the formation of BMMSC-generated BM niches through upregulation of beta-catenin, implying that the PDGF pathway contributes to the formation of ectopic BM. These results indicate that the BMMSC-organized BM niche system represents a unique hematopoietic progenitor resource possessing potential clinical value.
  • Yasuo Miura, Masako Miura, Stan Gronthos, Matthew R. Allen, Chunzhang Cao, Thomas E. Uveges, Yanming Bi, Driss Ehirchiou, Angela Kortesidis, Songtao Shi, Li Zhang
    Proceedings of the National Academy of Sciences, 102(39) 14022-14027, Sep 19, 2005  
    Osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo , whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis.
  • Yasuo Miura, Yumi Tohyama, Terutoshi Hishita, Amitabha Lala, Ernesto De Nardin, Yataro Yoshida, Hirohei Yamamura, Takashi Uchiyama, Kaoru Tohyama
    BLOOD, 96(5) 1733-1739, Sep, 2000  Peer-reviewed
    The roles of the protein tyrosine kinases Pyk2 (also called RAFTK or CAK beta) and Syk in the process of functional activation of human myeloid cells were examined. During granulocytic differentiation of HL-60 cells with dimethyl sulfoxide (DMSO), the amounts of Pyk2 and beta 2 integrin increased, whereas the amount of Syk was abundant before differentiation and did not change during differentiation. When the granulocytic cells were stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), tyrosine phosphorylation of Pyk2 occurred promptly and subsequent association of Pyk2 with beta 2 integrin was detected. In contrast, Syk was not tyrosine phosphorylated by fMLP Introduction stimulation but constitutively associated with beta 2 integrin, Stimulation with fMLP also caused the alteration of beta 2 integrin to an activated form, a finding that was confirmed by the observation of fMLP-induced cell attachment on fibrinogen-coated dishes and inhibition of this attachment by pretreatment with anti-beta 2 integrin antibody. Cell attachment to fibrinogen caused the enhanced tyrosine phosphorylation of Pyk2 and the initial tyrosine phosphorylation of Syk, which was also inhibited by pretreatment with anti-beta 2 integrin antibody. In vitro kinase assays revealed that Pyk2 and Syk represented kinase activities to induce tyrosine phosphorylation of several molecules in the anti-beta 2 integrin immunoprecipitates of the attached cells. These results showed that Pyk2 is involved in the functional activation of granulocytic cells in 2 signaling pathways: an fMLP receptor-mediated "inside-out" signaling pathway that might cause beta 2 integrin activation and a subsequent beta 2 integrin-mediated "outside-in" signaling pathway. Syk was activated in relation to cell attachment to fibrinogen as a result of "outside-in" signaling, although it was already associated with beta 2 integrin before fMLP stimulation. (C) 2000 by The American Society of Hematology.

Misc.

 82

Presentations

 2

Research Projects

 10

Other

 1
  • ①エクソソームを含む細胞外小胞を応用した免疫・血液病態の制御 ②間葉系幹細胞を応用した細胞治療開発 ③診療用電子デバイスに搭載可能な輸血アプリ *本研究シーズに関する産学共同研究の問い合わせは藤田医科大学産学連携推進セン ター(fuji-san@fujita-hu.ac.jp)まで