Future Projects(2023/4~)

  1. Understanding the interaction between the skin microbiota and the host and elucidating the mechanism of skin disease development
  2. Development and Application of Scaffold Materials to Accelerate Tissue Regenerative Medicine Research
  3. Exploration of scaffold materials for the construction of human iPS cell-derived cardiac tissue and their application to the treatment of cardiac diseases
  4. Mechanisms of liver fibrosis progression and repair via inter-organ networks
  5. Establishment of Novel Antigen-Specific Regulation of Autoimmune Diseases
  6. Establishment of disease control methods by detailed analysis of antigen specificity in autoimmune diseases

Understanding the interaction between the skin microbiota and the host and elucidating the mechanism of skin disease development

  • Keio University Co-leader: Prof. Masayuki Amagai (Dept. of Dermatology, School of Medicine)
  • JSR Corp. Co-leader: Jun Isayama
  • Project Period: Oct 2017 – *
    *including the 1st period of strategic projects (Oct 2017 – Sep 2022)

Background

Human skin harbors a wide variety of microorganisms, forming niches in which the predominant microbiota varies depending on the physiological state of the skin (moisture content, sebum content, inflammation, etc.) and structure (stratum corneum thickness, condition, frequency of turnover, etc.). It has been reported that these indigenous skin microorganisms are associated with the onset, exacerbation, remission, and other pathological changes of various skin diseases through their interactions with each other and with the host. However, the details of these interactions have not been fully elucidated.

Objectives

Our research group is conducting collaboration for establishing the new drug modalities targeting the skin microbiota. As a basis for this final goal, we are elucidating the relationship between changes in the indigenous skin microbiota and pathological changes through detailed analysis of human skin samples obtained from clinical practice. We are also experimentally analyzing the interactions between the microbiota and the host and between the microorganisms to understand the mechanisms of how the microbiota influence the host skin conditions.

Development and Application of Scaffold Materials to Accelerate Tissue Regenerative Medicine Research

  • Keio University Co-leader: Asst. Prof. Hiroshi Yagi (Dept. of General and Gastroenterological Surgery, School of Medicine)
  • JSR Corp. Co-leader: Satoshi Nakamura
  • Project Period: Oct 2017 – *
    *including the 1st period of strategic projects (Oct 2017 – Sep 2022)

Background

Regenerative medicine research has made remarkable progress in recent years, producing excellent results in disease modeling and drug discovery research in both academic and practical fields. Despite social expectation, however, its clinical application has not been realized yet. There is difficulty in achieving stable long-term engraftment of the transplanted cells due to physical/immunological stresses and/or insufficient blood flow in the transplanted area, resulting in insufficient functionality for regenerative medicine.

Objectives

The scaffold materials, one of three major elements of regenerative medicine, can provide environment suitable for the cells to grow and express their functions. An ideal scaffold material is expected to facilitate stable engraftment and self-organization of the cells, leading to regeneration of the damaged organs, by improving the above-mentioned deficiencies as well as promoting the migration of the host cells to the transplantation site. Our group has demonstrated that "decellularized tissue," in which cell nuclei and cell membrane components are removed from animal organs and tissues, and its gelated material shows beneficial characteristics as an excellent scaffold material mentioned above. In this study, we aim to put these materials to practical use by (1) optimizing the material preparation process, (2) understanding their quality and characteristics, and (3) linking the material properties to biological functions.

Exploration of scaffold materials for the construction of human iPS cell-derived cardiac tissue and their application to the treatment of cardiac diseases

  • Keio University Co-leader: Asst. Prof. Shugo Tohyama (Dept. of Caridiology, School of Medicine; to Mar. 2024); Prof. Hideyuki Shimizu (Dept. of Cardiovascular Surgery, School of Medicine; from Apr. 2023)
  • JSR Corp. Co-leader: Satoshi Nakamura
  • Project period: Apr. 2023 –

Background

Heart transplantation is currently the only approved treatment for severe heart failure. However, it has not become one of the standard therapies in Japan due to a serious shortage of donors. Regenerative medicine is one of the promising alternative approaches, and human induced pluripotent stem cells (hiPSCs) are particularly expected as its cell sources. Dr. Tohyama, the core member of this project, and his colleagues have established a series of technologies for hiPSC-based cardiac regenerative medicine, including the establishment of hiPSCs, their efficient proliferation and mass production/purification of hiPSC-derived cardiomyocyte (hiPSC-CMs), as well as the formation of cardiac spheroids/organoids. On the other hand, the efficiency of hiPSC-CM engraftment and suppression of post-transplant induced arrhythmias still need to be improved for the realization of the therapy.

Objectives

Prior studies by Dr. Tohyama’s team have supported the hypothesis that the construction and maturation of microvasculature promoted by the scaffold materials will improve efficiency in hiPSC-CM engraftment. This study aims to evaluate the scaffold materials developed at JKiC for this purpose. We expect our material to solve the technical problems for the development of hiPSC-based cardiac regenerative therapy.

Mechanisms of liver fibrosis progression and repair via inter-organ networks

  • Keio University Co-leader: Assoc. Prof. Nobuhiro Nakamoto (Dept. of Gastroenterology and Hepatology, School of Medicine)
  • JSR Corp. Co-leader: Shoichi Katoh
  • Project Period: Apr. 2023 -

Background

Due to westernization of diet and lack of exercise, NAFLD (nonalcoholic fatty liver disease) and NASH (nonalcoholic steatohepatitis), which are liver disorders caused by obesity and lifestyle-related diseases, have been increasing in Japan in recent years. NASH, like other viral liver diseases, progresses to liver fibrosis and cirrhosis and is associated with a high rate of liver cancer (hepatocellular carcinoma; HCC). Early intervention is urgently needed. However, the main therapeutic interventions for NASH are diet and exercise therapy, and the only drug therapies indicated by insurance in Japan are pioglitazone, an insulin-resistance improving drug, and vitamin E preparations.

Objectives

Liver fibrosis has been considered to be irreversible, but in recent years, various research approaches have revealed that there is a mechanism to repair the liver fibrosis. Using a mouse model of NASH repair, Dr. Nakamoto, the co-leader of our group, found that resident memory T cells (Trm) play a fundamental role in the repair process of liver fibrosis. In this project, we will extend the previous studies to analyze NASH fibrosis repair from multiple perspectives and in an integrated manner. Through this research, we aim to deepen understanding of the NASH fibrosis repair phenomenon and ultimately create research seeds contributing to treatment and diagnosis of NASH.

Establishment of Novel Antigen-Specific Regulation of Autoimmune Diseases

  • Keio University Co-leader: Assoc. Prof. Hayato Takahashi (Dept. of Dermatology, School of Medicine)
  • JSR Corp. Co-leader: Seiki Wakui
  • Project period: April 2023 -

Background

Pemphigus is an autoimmune blistering disease induced by IgG-type autoantibodies. Its target antigen, desmoglein, is a protein responsible for cell adhesion of epidermal keratinocytes. In patients with pemphigus, autoantibodies against desmoglein disrupt this cell adhesion function, resulting in the appearance of blisters in the epidermis that are called acantholysis. Currently, steroids and immunosuppressive, such as rituximab, are used to treat pemphigus, but these drugs work in an antigen nonspecific manner. Even though the antigen of autoantibodies in pemphigus has been identified, antigen-specific therapy has not yet been applied clinically for this disease. This project aims to analyze the pathogenesis of pemphigus in detail, focusing on antigen-specific immune cells, and to establish antigen-specific therapies in the future.

Objectives

The Department of Dermatology, Keio University School of Medicine has a long history of pemphigus research to elucidate its pathophysiology aiming at better and more advanced treatment in the future. In particular, we have developed a pemphigus mouse model and analyzed its antigen-specific reaction. By combining this knowledge with cutting-edge technologies owned by the JSR Group, we aim to detect the immune cells that cause this disease and to analyze their characters at the molecular level. In addition, our research group is engaged to establish the concept of antigen-specific therapies using our mouse models and to explore the potential for human application. We hope to present a completely new therapeutic strategy targeting specifically the immune cells that cause the disease and to establish the technology that can be applied not only to pemphigus but also to the treatment of many other autoimmune diseases.

Establishment of disease control methods by detailed analysis of antigen specificity in autoimmune diseases

  • Keio University Co-leader: Asst. Prof. Masaru Takeshita (Div. of Rheumatology, Dept. of Internal Medicine, School of Medicine)
  • JSR Corp. Co-leader: Seiki Wakui
  • Project period: April 2023 –

Background

Autoimmune disease are diseases caused by immune cells such as lymphocytes attacking the self. The presence of autoantibodies in the serum of patients is one of the characteristics of autoimmune diseases. The determination of the type of autoantibodies is diagnostically important because such information allows us to deduce the phenotype of the disease and to predict the prognosis including response to treatment. Since the amount of some types of autoantibodies is actually correlated to the disease activity, the appearance of autoantibodies is closely associated with disease pathogenesis.

The Division of Rheumatology has traditionally conducted autoantibody research, and identified many autoantibodies used in clinical practice. One of our research targets is Sjögren's syndrome, and we have focused on the lesion sites where disease-induced changes are most pronounced. Like many other autoimmune diseases, a clear etiology has not been established in Sjögren's syndrome yet. Therefore, pan-immunosuppressive therapies are mainly conducted, in which the side effects such as infections are concerned.


Objectives

Previous studies have revealed that patients with Sjögren's syndrome have autoimmune reactions due to infiltration of autoreactive B cells at the lesion site. This study aims to elucidate the etiology of Sjögren's syndrome, and to develop antigen-specific immunosuppressive therapy and companion diagnostics by combining the advanced biotechnologies of the JSR Group with the knowledge about Sjögren's syndrome accumulated by research activities of the Division of Rheumatology.