Bio

Professional Education


  • Bachelor of Science, University Of Tokyo (2007)
  • Master of Science, University Of Tokyo (2009)
  • Doctor of Philosophy, University Of Tokyo (2012)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Stem Cell and iPS Cell Biology for Regenerative Medicine

Publications

Journal Articles


  • Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. Leukemia Sakurai, M., Kunimoto, H., Watanabe, N., Fukuchi, Y., Yuasa, S., Yamazaki, S., Nishimura, T., Sadahira, K., Fukuda, K., Okano, H., Nakauchi, H., Morita, Y., Matsumura, I., Kudo, K., Ito, E., Ebihara, Y., Tsuji, K., Harada, Y., Harada, H., Okamoto, S., Nakajima, H. 2014

    Abstract

    Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.Leukemia advance online publication, 13 May 2014; doi:10.1038/leu.2014.136.

    View details for DOI 10.1038/leu.2014.136

    View details for PubMedID 24732596

  • Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation CELL STEM CELL Nishimura, T., Kaneko, S., Kawana-Tachikawa, A., Tajima, Y., Goto, H., Zhu, D., Nakayama-Hosoya, K., Iriguchi, S., Uemura, Y., Shimizu, T., Takayama, N., Yamada, D., Nishimura, K., Ohtaka, M., Watanabe, N., Takahashi, S., Iwamoto, A., Koseki, H., Nakanishi, M., Eto, K., Nakauchi, H. 2013; 12 (1): 114-126

    Abstract

    Adoptive immunotherapy with functional T cells is potentially an effective therapeutic strategy for combating many types of cancer and viral infection. However, exhaustion of antigen-specific T cells represents a major challenge to this type of approach. In an effort to overcome this problem, we reprogrammed clonally expanded antigen-specific CD8(+) T cells from an HIV-1-infected patient to pluripotency. The T cell-derived induced pluripotent stem cells were then redifferentiated into CD8(+) T cells that had a high proliferative capacity and elongated telomeres. These "rejuvenated" cells possessed antigen-specific killing activity and exhibited T cell receptor gene-rearrangement patterns identical to those of the original T cell clone from the patient. We also found that this method can be effective for generating specific T cells for other pathology-associated antigens. Thus, this type of approach may have broad applications in the field of adoptive immunotherapy.

    View details for DOI 10.1016/j.stem.2012.11.002

    View details for Web of Science ID 000313839500015

    View details for PubMedID 23290140

  • Stepwise Development of Hematopoietic Stem Cells from Embryonic Stem Cells PLOS ONE Matsumoto, K., Isagawa, T., Nishimura, T., Ogaeri, T., Eto, K., Miyazaki, S., Miyazaki, J., Aburatani, H., Nakauchi, H., Ema, H. 2009; 4 (3)

    Abstract

    The cellular ontogeny of hematopoietic stem cells (HSCs) remains poorly understood because their isolation from and their identification in early developing small embryos are difficult. We attempted to dissect early developmental stages of HSCs using an in vitro mouse embryonic stem cell (ESC) differentiation system combined with inducible HOXB4 expression. Here we report the identification of pre-HSCs and an embryonic type of HSCs (embryonic HSCs) as intermediate cells between ESCs and HSCs. Both pre-HSCs and embryonic HSCs were isolated by their c-Kit(+)CD41(+)CD45(-) phenotype. Pre-HSCs did not engraft in irradiated adult mice. After co-culture with OP9 stromal cells and conditional expression of HOXB4, pre-HSCs gave rise to embryonic HSCs capable of engraftment and long-term reconstitution in irradiated adult mice. Blast colony assays revealed that most hemangioblast activity was detected apart from the pre-HSC population, implying the early divergence of pre-HSCs from hemangioblasts. Gene expression profiling suggests that a particular set of transcripts closely associated with adult HSCs is involved in the transition of pre-HSC to embryonic HSCs. We propose an HSC developmental model in which pre-HSCs and embryonic HSCs sequentially give rise to adult types of HSCs in a stepwise manner.

    View details for DOI 10.1371/journal.pone.0004820

    View details for Web of Science ID 000265496400002

    View details for PubMedID 19287487

  • Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice NATURE IMMUNOLOGY Nagawa, F., Kishishita, N., Shimizu, K., Hirose, S., Miyoshi, M., Nezu, J., Nishimura, T., Nishizumi, H., Takahashi, Y., Hashimoto, S., Takeuchi, M., Miyajima, A., Takemori, T., Otsuka, A. J., Sakano, H. 2007; 8 (2): 206-213

    Abstract

    Jawless vertebrates have acquired immunity but do not have immunoglobulin-type antigen receptors. Variable lymphocyte receptors (VLRs) have been identified in lamprey that consist of multiple leucine-rich repeat (LRR) modules. An active VLR gene is generated by the assembly of a series of variable gene segments, including many that encode LRRs. Stepwise assembly of the gene segments seems to occur by replacement of the intervening DNA between the 5' and 3' constant-region genes. Here we report that lamprey (Lethenteron japonicum) assemble their VLR genes by a process involving 'copy choice'. Regions of short homology seemed to prime copying of donor LRR-encoding sequences into the recipient gene. Those LRR-encoding germline sequences were abundant and shared extensive sequence homologies. Such genomic organization permits initiation of copying anywhere in an LRR-encoding module for the generation of various hybrid LRRs. Thus, a vast repertoire of recombinant VLR genes could be generated not only by copying of various LRR segments in diverse combinations but also by the use of multiple sites in an LRR gene segment for priming.

    View details for DOI 10.1038/ni1419

    View details for Web of Science ID 000243597600019

    View details for PubMedID 17187071

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