Outline Research Education
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Staffs

Title Name Researcher information
Professor OHTEKI Toshiaki
Associate Professor SATO Taku
Assistant Professor Masashi Kanayama
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Outline

 Our research projects focus on understanding the dynamic maintenance and transfiguration of homeostasis in the living body. Our goal is to define the homeostasis mechanism under conditions of health and disease. To accomplish this goal, we are trying to clarify the molecular basis of induction and failure of homeostasis by focusing on immune cells in particular myeloid cells (dendritic cells and macrophages), tissue stem cells, and their functional interplay in the immunological and non-immunological organs. On the basis of our findings, we will further pursue our research in the hope of developing new rational therapies for prevention and treatment of disease.
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Research

1. Research on myeloid cells
1) Identification of novel sources of mononuclear phagocytes
 Mononuclear phagocytes contain monocytes, macrophages and dendritic cells (DCs). In a recent decade, it has been continuing epoch-making discoveries in the field of mononuclear phagocytes and their functions are now beyond classical Immunology and extend to broad life phenomenon, e.g. tissue development/regeneration, wound-healing, and establishment of tumor environments and various inflammatory diseases.
DCs consist of conventional DCs (cDCs) and plasmacytoid DCs (pDCs), both of which play critical regulatory roles in the immune system. cDCs exhibit prominent antigen-presenting ability, whereas pDCs are characterized by their capacity to produce large amounts of type I interferons (IFNs). We have discovered the DC progenitors in the mouse bone marrow, and named common DC progenitors (CDPs) (Immunity 2013; Nat Immunol 2007). Interestingly, CDPs are divided into 2 subpopulations. One is M-CSF receptor (R)+ CDPs mainly producing cDCs, and the other M-CSFR-CDPs producing a large number of pDCs. In addition to CDPs, common monocyte/macrophage progenitors, cMoP, identified in the mouse bone marrow and spleen by other group in 2013.
Based on these achievements in mouse, we have been trying to identify human progenitors of mononuclear phagocytes, and most recently succeeded to identify human cMoP (Immunity 2017; Int Immunol 2018). Human cMoP gives rise to only monocytes but not other hematopoietic cells including DCs. Given that monocytes and monocyte-derived macrophages cause a variety of inflammatory disorders, including metabolic syndromes and tumor development, our studies shed light on possible therapeutic applications for infectious diseases, cancers and autoimmune diseases. Collaborations with pharmaceutical company and Department of Hematology of TMDU toward the development of therapeutic agents targeting cMoP and monocyte lineage and with Department of Pediatrics of TMDU for the pathology clarification of congenital pulmonary alveolar proteinosis (PAP) are currently in progress.

2) Mechanism of brain function impairment by spatiotemporal transformation of microglial enhancer
 The decline in tissue regeneration and homeostasis associated with life-stage progression is closely related to the functional alteration of macrophages. Microglia, a macrophage in the brain, is actively contributing to the brain development and maintenance during young age (regenerative microglia). However, with age, microglial inflammatory trait becomes prominent with impaired phagocytosis and brain-derived neurotrophic factor (BDNF) production etc (inflammatory microglia). As a result, functional neurons and synapses are decreased and destroyed. However, the overall picture and entire process of the microglial functional alteration and causative epigenomic transformation have not been clarified.
 In this study, using a novel technology that can detect the active enhancer region and its activity with high sensitivity, we will identify the super enhancers (hereafter, SEs) responsible for the microglial transformation during life-stage progression, and elucidate the entire process of transformation dynamics. As SEs are activated in a cell-type specific manner, one can expect that it will lead to the development of novel technology to specifically control the age-related functional alteration of microglia. To date, we have identified 36,320 new microglial enhancers including 937 regions that become different with age (unpublished).

3) Mechanism of emergency myelopoiesis
 Unlike steady-state hematopoiesis, hematopoiesis triggered at infection, irradiation and anti-cancer therapy is biased toward myeloid cell differentiation and production, that is “emergency myelopoiesis”. However, due to the fluctuation of cell-surface marker(s) on hematopoietic stem progenitor cells (HSPCs), it has long been difficult to understand bona-fide emergency myelopoiesis. Recently, our laboratory succeeded in identifying a novel marker with less fluctuation during emergency myelopoiesis. Using this unique marker, we will elucidate the mechanism of emergency myelopoiesis.

2. Research on tissue stem cells
1) Understanding of tissue homeostasis and its breakdown on the basis of immune cell-tissue stem cell interplay
 We found that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs), and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling, preserves the self-renewal and multi-lineage differentiation capacity of HSCs (Nat Med 2009). Based on this finding, we show that type I IFN preconditioning, without irradiation or DNA alkylating agents, significantly enhanced the HSC engraftment efficiency in wild type (WT) recipient mice (Blood 2013). Based on these achievements, we have further found that physiological levels of type I IFN signaling also affect other tissue stem cells (submitted).

2) Establishment of biobank for human tongue cancer
 Oral cancer has an increasing trend of 270,000 new cases per year worldwide. Two-thirds of them are tongue cancers, and in advanced cases, they become refractory to treatment and have a poor prognosis, and causal genes have not been identified. Under these backgrounds, we succeeded in establishing a human tongue cancer organoid culture system. In the future, we aim to develop fundamental technologies that lead to personalized treatment.
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Education

Immunology lectures in Faculty of Medicine, Masters Degree, and Doctoral Programs, Graduate School Seminar in other universities as a adjunct lecturer, and educational and research guidance for individual graduate students.
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