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.

1. Research on myeloid cells
1) Identification of novel sources of dendritic cells and macrophages
　 Dendritic cells (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) in response to viral and self-nucleic acids. We have discovered the DC progenitors in the mouse bone marrow, and named common DC progenitors (CDPs) (Immunity 2013; Nat Immunol 2007). Interestingly, we found that 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.
During stress response, monocytes actively influx into various tissues and differentiate into macrophages, which are involved in inflammation, tissue repair, and cancer growth. In addition to CDPs, we recently found human common monocyte progenitors (cMoPs) in human bone marrow and umbilical cord blood (Immunity 2017; Int Immunol 2018). Human cMoP gives rise to only monocytes but not other hematopoietic cells including DCs. Given that monocytes are involved in chronic myelomonocytic leukemia (CMML) and monocyte-derived tumor-associated macrophages (TAMs) promote tumor development, we, in collaboration with a pharmaceutical company, have generated an antibody-drug conjugate (ADC) that selectively targets human cMoP. When this ADC was administered to the CMML PDX model, leukemia cells almost completely disappeared from the bone marrow and peripheral blood. In addition, upon ADC administration into tumor-bearing humanized mice, both peripheral blood monocytes and intratumoral TAMs disappeared, leading to the shrinkage of tumor mass (Front Immunol 2021). Since monocytes are also involved in various inflammatory diseases, the application of human monocyte lineage-specific ADCs to these diseases is also expected.


2) Impairment of brain function by microglial enhancer in aging and Alzheimer’s disease (AD)
　 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.
　 Using a novel RIKEN technology that can detect the active enhancer region at single base level, we are trying to identify the enhancers responsible for the microglial transformation during life-stage progression and AD development. To date, we have succeeded to identify 36,320 new microglial enhancers including 937 regions that become different with age, and the analysis of coding regions regulated by the enhancers using Hi-C technology is in progress. As enhancers are activated in a cell-type specific manner, one can expect the development of novel technology that specifically controls the age-related functional alteration of microglia.


2. Research on tissue stem cells
1) Tissue homeostasis and its breakdown on the basis of immune cell-tissue stem cell interplay
　Even under the steady-state, type I interferons (IFNs) are consistently produced, albeit in trace amounts, so called “physiologic type I IFNs”. We previously reported that the physiologic 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 achievement, we examined the significance of physiologic type I IFNs in intestinal stem cells (ISCs) and found that it reduces the number and function of ISCs, resulting in the promoted differentiation into secretory progenitors (Nat Cell Biol 2020). Similarly, physiologic type I IFNs impaired the stemness of colonic stem cells (CSCs), leading to the defective colonic regeneration with lethality in a DSS colitis model (Sci Rep 2020).
Although several types of cells are synchronously involved in the damage-induced epithelial regeneration, it remains unclear to what degree each population contributes to the overall epithelial regeneration. Using a combination of genetic lineage tracing, single-cell gene expression profiling, and organoid-formation assays, we characterized the heterogeneity of epithelial stem cells in the radiation-damaged intestine. As a result, we found that the main cell of origin after intestinal injury originated from Lgr5+ cells (Sci Rep 2020).

2) Establishment of human tongue cancer organoid biobank
　Squamous cell carcinoma occurs in the oral cavity, esophagus, lungs, and cervix. Tongue cancer accounts for about 60% of oral cancer, and the 5-year survival rate is extremely low for advanced tongue cancer, and the recurrence rate after radical treatment is also high. Similarly, squamous cell carcinoma of the esophagus, which is characteristic of Asian countries including Japan, has a very high recurrence rate after curative treatment. As a multicenter collaborative study, our research group has succeeded in constructing an organoid library specialized for human tongue cancer and human esophageal squamous cell carcinoma, which has never been reported (34 cases of tongue cancer and 18 cases of esophageal cancer, ongoing). In addition, we have established cancer organoids that are resistant to anticancer drugs used in clinical treatment (4 cases of tongue cancer and 4 cases of esophageal cancer, ongoing). Using these unique resources, the elucidation of the mechanism for acquiring anticancer drug resistance and the search for drug discovery are in progress.

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.