Recent Progress in iPSC Research and Application
Abstract
        Induced pluripotent stem cells (iPSCs) can proliferate almost indefinitely and differentiate into multiple lineages. They are used worldwide for novel cell-based therapies, disease models, and drug discovery.
        In our basic research at the iPS Cell Research Center at Gladstone Institutes, one of the On-site Laboratories of Kyoto University, we are focusing on clarifying the mechanisms of protein translational regulation in the proliferation and differentiation of iPSCs. We have previously reported that the translation regulator NAT1 is essential for the self-renewal and neuronal differentiation of human iPSCs.
        As translational research, we are proceeding with an iPSC stock project in which clinical-grade iPSC clones are being established from healthy donors with homologous HLA haplotypes to lower the risk of transplant rejection. We started distributing the iPSC stock to domestic and overseas institutions, and related clinical studies have begun for age-related macular degeneration, Parkinson’s disease, and other diseases, giving the expectation that iPSC-based regenerative medicine will be widely used in the future. Additionally, we reported HLA gene-edited iPSCs that could expand the range of patients who benefit from iPSC therapies faster than the homologous HLA haplotype strategy.
　　Other applications of iPSCs include drug screening, toxicity studies, and the elucidation of disease mechanisms using disease-specific iPSCs from patients. iPSCs established from patients contain a complete set of the genes that resulted in the disease and thus represent a new disease model that complements or in some cases replaces animal models. Indeed, accumulating evidence is demonstrating the benefits of iPSCs in drug repositioning, and several clinical studies have begun for fibrodysplasia ossificans progressiva, amyotrophic lateral sclerosis, and other diseases.
        Over the past decade, iPSC research has made great progress, moving toward innovative therapeutics for people with intractable diseases by the application of new findings from basic science and reverse translation from clinics.

Biography
      Shinya Yamanaka, MD, Ph.D., is Director Emeritus and Professor of the Center for iPS Cell Research and Application (CiRA) at Kyoto University and Professor of anatomy at UC San Francisco. He is also Senior Investigator and the L.K. Whittier Foundation Investigator in Stem Cell Biology at Gladstone Institutes, as well as Representative Director of the Public Interest Incorporated Foundation, CiRA Foundation. The iPS Cell Research Center at Gladstone Institutes, one of the On-site Laboratories of Kyoto University, was established in 2019. He is most recognized for his original research on induced pluripotent stem cells (iPSCs). Since his breakthrough finding, he has been the recipient of many prestigious awards, including the Nobel Prize in Physiology or Medicine (2012).

Cell Rejuvenation and Disease
Abstract
        Aging is characterized by the functional decline of tissues and organs and the increased risk of aging-associated disorders. Several ‘rejuvenating’ interventions have been proposed to delay aging and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the aging process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. I will discuss some of epigenetic changes that occur during aging and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and will outline questions to guide future research on interventions to rejuvenate the epigenome and delay aging processes.

Biography
        Dr. Juan Carlos Izpisua Belmonte, previously  the Roger Guillemin Chair and Professor in the Gene Expression Laboratory at Salk Institute for Biological Studies, is currently Director of Altos Labs Institute of Science in San Diego. During life’s early stages cells display high levels of plasticity, regeneration and resilience against stress, disfunction and injury, which are key features of human health. Dr. Juan Carlos Izpisua Belmonte, has contributed towards understanding the molecular basis underlying embryogenesis and early postnatal life, as well as gained insights into how to program and rejuvenate adult and diseased cells. He is developing technologies to program cells to states similar to those observed in the early, healthy stages of life, with the objective of developing universal health therapeutics to overcome human.

iPS cell-based therapy for Parkinson’s disease
Abstract
        Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson's disease (PD). Towards the clinical application of iPSCs, we have developed a method for 1) scalable DA neuron induction on human laminin fragments and 2) sorting DA progenitor cells using a floor plate marker, CORIN. The grafted CORIN+ cells survived well and functioned as midbrain DA neurons in the 6-OHDA-lesioned rats and showed a minimal risk of tumor formation. In addition, we performed a preclinical study using primate PD models. Regarding efficacy, human iPSC-derived DA progenitor cells survived and functioned as midbrain DA neurons in MPTP-treated monkeys. Regarding safety, cells sorted by CORIN did not form any tumors in the brains for at least two years. Moreover, we found that MRI and PET imaging was useful in monitoring the survival, expansion, and function of the grafted cells as well as the immune response by the host brain. Based on these results, we started a clinical trial to treat PD patients at Kyoto University Hospital in Kyoto, Japan, in 2018. The trial evaluates the safety and efficacy of transplanting human iPS cell-derived DA progenitors into PD patients' putamen. Using a stereotaxic surgical technique, we implant approximately 5 or 10 million cells into the bilateral putamen of the patients. The target is seven patients, and we will observe each of them for two years. The trial is now ongoing without any severe adverse events.

Biography
        Jun Takahashi is a director and professor of the Center for iPS Cell Research and Application (CiRA) at Kyoto University, Kyoto, Japan. He graduated from the Kyoto University Faculty of Medicine in 1986 and started his career as a neurosurgeon at Kyoto University Hospital. After earning his Ph.D. from the Kyoto University Graduate School of Medicine, he worked as a postdoctoral research fellow at the Salk Institute (Dr. Fred Gage), CA, U.S.A., where he started research on neural stem cells. After returning to Kyoto University Hospital, he conducted functional neurosurgery, including deep brain stimulation and also research work on stem cell-based therapies. In 2012, he became a full professor at CiRA, pursuing stem cell therapies for Parkinson’s disease patients.

Cancer Radiotherapy at the Tip of Endoscope Driven by Laser Wakefield Acceleration
Abstract
        Laser wakefield acceleration (LWFA) [1] is capable of accelerating electrons over a compact distance than any conventional accelerators. Ion top of this the recent development of the high density (HD) regime of LWFA allows the relatively low energy electron acceleration over a microscopic distance with higher efficiency [2]. This HD-LWFA introduces new operations and opportunities of radiotherapy by electrons and we may take a radiotherapy using the endoscope (LWFA via a fiber laser at its tip), in which a surgeon may look tissues via endoscope and zap electrons in front of its target inside a patient body [3]. Because of the HD-LWFA is so tiny (and also more efficient) than the regular gaseous LWFA and certainly conventional accelerators, its structure may fit such a tiny confine (and all solid state) operation. This may be also regarded as a future replacement of a Brachytherapy. The emitted electrons can be preferentially stopped at or near vector-medicine guided cancer cells [4]. These can be also applicable to surface tissues such as skin cancer.  We will discuss the physical properties of HD-LWFA, its laser technology, and how best we can look for radiotherapy and nuclear medicine applications in our presentation.
[1] T. Tajima and J. Dawson, Phys. Rev. Lett. 43, 267 (1979).
[2] E. Barraza et al., Photonics 9, 476 (2022).
[3] D. Roa et al., Photonics 9, 403 (2022). 
[4] Y. Higashi et al., Sci. Rpt. 11, 14192 (2021).

Biography
        Toshiki Tajima (with John Dawson) suggested in 1979 the concept and theory of the formation of a wakefield behind a laser pulse and its subsequent compact acceleration of particles to high energies. He was among the first team that experimentally demonstrated this concept in 1994. This concept spurred the creation of the field now referred to palm size (and now pencil-tip size) medical accelerators. These include cancer radiotherapy (including electrons, ions, and X-rays). These electrons can also produce neutrons, which can make compact radio-isotopes for nuclear medicine applications.

Unbiased screening approaches to explore the field of biomedical sciences
Abstract
        Cells establish the asymmetrical distribution of molecules across membranes using ATP as an energy and quickly alter this asymmetrical distribution to adopt to the environmental changes. In the case of ions, sodium and calcium ions are exported to the extracellular space, and this electrochemical gradient is utilized to activate cells. In the case of lipids, the phospholipid phosphatidylserine (PS) is distributed restrictively to the inner side of lipid bilayers on the plasma membrane in living cells while is exposed on the cell surface when cells are activated or undergo cell death. The exposed PS is used as a scaffold for chemical reaction or a signal for removal of dead cells. When PS is exposed from the inner side, cell surface lipids such as phosphatidylcholine and sphingomyelin are internalized. Because lipids are non-specifically and bi-directionally distributed, this process is called as lipid scrambling and proteins responsible for this process called scramblases. However, molecular identity of scramblases was unknown for decades. To unveil the secrets of lipid scrambling, we used unbiased screening approaches and identified the long-sought after scramblase(s), their chaperones, activators, and regulators. To identify such factors from dying cells, we first thought to utilize a screening system using CRISPR sgRNA library. However, needless to say, dying cells do not proliferate, which prevent enrichment of desired sgRNAs during the screening process. To overcome this problem, we established a novel screening system, which we call “Revival Screening”. Using this system, now we can identify factors from dying cells, non-proliferating cells, and even tissues in living animals. In this talk, I will introduce the system and talk about its potential application to the field of biomedicine.

Biography
        After obtaining Ph.D. from Graduate School of Medicine, Osaka University in 2007 (trained in Dr. Hidesaburo Hanafusa & Dr. Tatsuo Takeya Lab), he joined Dr. Shigekazu Nagata Lab in Kyoto University as a postdoc. He was then promoted to an Assistant Professor at Graduate School of Medicine, Kyoto University in 2010, an Associate Professor at Immunology Frontier Research Center, Osaka University in 2015, and a Professor at iCeMS, Kyoto University in 2017. He then became a Deputy director of iCeMS, a Professor of Graduate School of Biostudies in 2017, and established an on-site laboratory at Academia Sinica, Taiwan in 2019. 

Aging of Immunity and Immunity in Aging 

Abstract
        Aging is increasingly associated with reduced acquired immunity and chronic inflammatory disorders often with autoimmunity, however possible relationship of the apparently paradoxical features, if any, remains elusive. With age, aberrant lymphocyte subpopulations are progressively increased in both T- and B-cell compartments; CD4+ T cells constitutively expressing PD-1 and CD153 (CD30R), termed senescence-associated (SA-) T cells, and B cells unusually expressing CD11c and CD30, called aging-related B cells (ABCs). SA-T cells show characteristic features of cell senescence and are defective of T-cell receptor (TCR)-mediated activation and proliferation, while ABCs exhibit an apparent propensity for autoantibody production. We found that, when SA-T cells meet ABCs in given tissues, the two cell types are mutually activated for the proliferation via the engagement of respective CD153 and CD30, leading to the secretion of abundant proinflammatory cytokines being reminiscent of senescence-associated secretory phenotype and the production of autoantibodies, respectively, in a self-amplifying manner with age. Importantly, the reaction incidence may be robustly exaggerated in various tissues under diverse endogenous or exogenous stresses, including metabolic stresses such as high-fat diet, chronic tissue injuries such as hypoxia and congestion, and certain genetic predispositions. As such, for instance, the development and progression of lupus disease in lupus-prone female mice are remarkably ameliorated with significantly improved survival rate by the specific blockade of CD153/CD30 interaction. We propose that the self-amplifying mutual activation of potentially pathogenic age-associated lymphocyte subpopulations in tissues under diverse stresses underlines various age-associated common chronic diseases. Specific blockade of CD153/CD30 interaction may be beneficial for controlling devastating progression of age-associated chronic diseases in humans.

Biography
        Nagahiro Minato is the president of Kyoto University. Born in 1951, Minato holds a doctorate in medicine from Kyoto University, and served as the dean of its Faculty and Graduate School of Medicine from 2010 until 2014, when he was appointed as executive vice-president for strategy coordination, research, planning, and hospital administration. In October 2017, he was also appointed as the university’s provost, and subsequently elected as president in October 2020. His field of academic specialization is immunology. He has published approximately 220 scientific papers throughout his career, and he contributed to the development of checkpoint blockade cancer immunotherapy in collaboration with Nobel laureate Dr. Tasuku Honjo.

Memory responses by innate-like T cells
Abstract
        Some types of T lymphocytes are considered similar to cells of the innate immune system, because of their immediate and apparently hard-wired responses.  An example of innate-like T cells is mucosal associated invariant T (MAIT) cells, and we have examined if these cells undergo long-term changes exemplified by increased responses, similar to memory CD4 and CD8 T cells.  We tested MAIT cells after bacterial infection. Mouse MAIT cells include IL-17 producing (MAIT17) and IFNγ-producing (MAIT1) subsets.  These are maintained after infection, but they are increased in number and they are more antigen responsive, long after the bacterial challenge has been cleared.  The memory-like MAIT cells undergo long-term changes in their transcriptional landscape and transcriptomes.  The MAIT cell subsets also differ for their metabolic state.  For example, antigen-exposed IL-17 producing mouse MAIT cells (MAIT17) have higher lipid uptake, lipid storage and mitochondrial potential compared to IFNγ-producing MAIT1 cells.  Furthermore, different types of responses by these cells have different metabolic requirements.  An in vitro analysis shows that antigen stimulation of their TCRs is more dependent on mitochondrial activity.  Typical of innate-like cells, MAIT cells also respond independently of antigen to IL-12 plus IL-18 to produce IFNγ.  This cytokine-mediated response is heavily dependent on glycolysis.  In conclusion, our data indicate that innate-like T cells are capable of physiologic alterations to attain a memory-like state, and that metabolism influences the responses of the memory-like subsets of MAIT cells. 

Biography
        Mitchell Kronenberg received a Ph.D. from the California Institute of Technology and was on the faculty of the UCLA School of Medicine (1986-1997).  He joined the La Jolla Institute for Immunology (LJI) and served as LJI President (2003-2021).  He is currently the LJI Chief Scientific Officer.  Dr. Kronenberg’s research interests include innate-like T cells, the regulation of mucosal immunology and the pathogenesis of inflammatory bowel disease. He has co-authored more than 400 publications, and is a fellow of the American Association for the Advancement of Science (AAAS), a Distinguished Fellow of the American Association of Immunologists, and recipient of an NIH MERIT award. He is an advisor to organizations including the Board of Scientific Counselors of the US National Cancer Institute.

From in vitro gametogenesis to human biology
Abstract
          The germ-cell lineage ensures the creation of new individuals, perpetuating/diversifying the genetic and epigenetic information across the generations.  We have been investigating the mechanism for germ-cell development, and have shown that mouse embryonic stem cells (mESCs)/induced pluripotent stem cells (miPSCs) are induced into primordial germ cell-like cells (mPGCLCs) with a robust capacity both for spermatogenesis and oogenesis and for contributing to offspring.  These works have served as a basis for elucidating key mechanisms during germ-cell development such as epigenetic reprogramming, sex determination, meiotic entry, and nucleome programming.
        By investigating the development of cynomolgus monkeys as a primate model, we have defined a developmental coordinate of pluripotency among mice, monkeys, and humans, identified the origin of the primate germ-cell lineage in the amnion, and have elucidated the X-chromosome dosage compensation program in primates.  Accordingly, we have succeeded in inducing human iPSCs (hiPSCs) into human PGCLCs (hPGCLCs) and then into oogonia with appropriate epigenetic reprogramming.  More recently, we have demonstrated an ex vivo reconstitution of fetal oocyte development in humans and monkeys.  These studies have established a foundation for human in vitro gametogenesis.
        Here, I would like to provide a brief overview of our work, including latest findings.  Building upon such progresses, I will discuss our ongoing endeavors toward promoting advanced studies of human biology.

Biography
        Mitinori Saitou received his M.D. and Ph.D. (under Prof. Shoichiro Tsukita) from the Kyoto University.  He performed his postdoctoral work at the Wellcome Trust/Cancer Research UK Gurdon Institute (with Prof. Azim Surani).  He was appointed team leader at the RIKEN Center for Developmental Biology in 2003.  He was appointed Professor at the Graduate School of Medicine, Kyoto University in 2009, and Director of the JST ERATO program in 2011. He was appointed Professor at the Kyoto University Institute for Advanced Study (KUIAS) and Director of the Institute for the Advanced Study of Human Biology (ASHBi) in 2018.  His work focuses on the mechanism and reconstitution in vitro of germ cell development in mice, non-human primates, and humans.

Biography
      Corinne Peek-Asa, Ph.D. is the Vice Chancellor for Research and Professor with Distinction of Epidemiology at the University of California, San Diego. She was formerly the Associate Dean for Research in the College of Public Health and the William Battershell Distinguished Professor at the University of Iowa. Dr. Peek-Asa’s research focuses on the epidemiology, implementation, and translation of programs and policies to prevent acute traumatic injuries and violence. She directs an NIH-funded International Trauma and Violence Research Training Program and was the Director of the CDC-funded Injury Prevention Research Center from 2004 to 2020. She is an elected member of the National Academy of Medicine and serves on the NAM Accelerating Progress in Traumatic Brain Injury Forum. She was a 2010 ResearchAmerica! Public Health Hero. The impact of VCR Peek-Asa’s work to reduce the burden of traumatic injury and violence led to numerous public health advancements, local and federal policies, and prevention programs.

Biography
      Kiichiro Tomoda, Ph.D., is a Program-Specific Research Center Associate Professor of the Center for iPS Cell Research and Application (CiRA) at Kyoto University and Research Investigator at Gladstone Institutes. His research focuses on how environmental signals impact the ability of human induced pluripotent stem (iPS) cells to grow and differentiate into specific cell types. He has recently focused on fundamental biological events in iPS cells, such as protein translation and small organelle homeostasis. More specifically, he is interested in protein translation initiation and uses an animal model to understand similarities and differences in protein translation regulation between stem cells and differentiated cells. He has been overseeing one of the On-site Laboratories of Kyoto University, iPS Cell Research Center at Gladstone Institutes, since 2020.

Biography
        Fuyuhiko Tamanoi is a biochemist who has a long-standing interest in Cancer Research and Therapy. He was the Director of Signal Transduction and Therapeutics program at Jonsson Comprehensive Cancer Center at UCLA from 1997 to 2017. He also served as Research Director at California NanoSystems Institute. In 2019, he established Quantum Nano Medicine Research Center at Kyoto University as an onsite lab with UCLA. The Center combines Particle Physics, Nanotechnology and Radiation therapy.
        His recent work at Kyoto University focuses on generating Auger and photoelectrons inside cancer cells to cause DNA double strand breaks and induce cell death. Based on this approach, he is developing a new type of radiation therapy.
        He received PhD in Molecular Biology from Nagoya University in 1977 and carried out a postdoctoral work at Harvard Medical School (1977-1980). He then worked at Cold Spring Harbor Laboratory (1980-1985) as a staff investigator. He joined the faculty at the University of Chicago (Assistant Professor, Associate Professor) (1985-1993). He moved to the University of California, Los Angeles and became Professor in 1997. He continues his affiliation at UCLA as a cross-appointment Professor in the Dept. of Microbiology and Molecular Genetics. In 2017, he joined Kyoto University as a program-specific Professor at the Institute for Integrated Cell-Material Sciences, Institute for Advanced Study. In 2019, he established Quantum Nano Medicine Research Center. 

Biography
        Dr. Gutkind is a Distinguished Professor and Chair, Department of Pharmacology, School of Medicine, and Associate Director for Basic Science at the Moores Cancer Center, University of California San Diego. His research team is exploiting the emerging information on dysregulated signaling circuitries and individual genomic and molecular alterations to develop new precision cancer therapies and multimodal immunotherapies. His research team has pioneered the study of G proteins and G protein coupled receptors in human malignancies, and discovered that aberrant activation of the PI3K-mTOR network is the most frequent dysregulated signaling mechanism in oral malignancies. As part of his translation efforts, Dr. Gutkind has led two multi institutional clinical trials establishing the benefits mTOR inhibition for oral cancer prevention and treatment. His honors include the NIH Merit Award, the Pharmaceutical Research and Manufacturers of America (PhRMA) Research & Hope Award, and his selection as Fellow of ASBMB and ASPET. He was elected in 2019 to the National Academy of Medicine, recognizing his team’s translational efforts in the area of cancer signaling. Dr. Gutkind has published over 550 research articles in some of the most prestigious journals, and has organized multiple national and international meetings and symposia. He has mentored many junior investigators, who are now playing leadership roles in multiple institutions in the United States and abroad

Biography
        Masatoshi Hagiwara was born in Mie prefecture, Japan and entered into Mie University School of Medicine in 1978. When he returned from the Salk Institute in 1993, he started his laboratory in Nagoya University School of Medicine as Assistant Professor. He moved to Tokyo in 1997 as Professor of the Medical Research Institute of Tokyo Medical and Dental University, and decided to try deciphering the splicing code to cure some genetic diseases caused by aberrant splicing. He moved to Kyoto University in 2010 as Professor of the Department of Anatomy and Developmental Biology in the Graduate School of Medicine. His long lasting dream is to save people suffering from incurable diseases with his own “magic bullets”.

Biography
        John M. Carethers, MD became the Vice Chancellor for Health Sciences at UC San Diego in January 2023. As Vice Chancellor, he oversees UC San Diego Health along with the School of Medicine, School of Public Health and School of Pharmaceutical Sciences to integrate, grow, and expand the missions of clinical excellence, education, discovery, and community engagement. Dr. Carethers is a trained gastroenterologist and physician-scientist who focuses his research in the area of hereditary colon cancer genetics and colon cancer disparities.

Biography
        Dr. Kaoru Kitajima is a botanist and forest ecologist, with ca. 40 years of research experience in tropical America, Asia and Africa. For the International Strategy Office of Kyoto University, she assists Director Kono and oversees its North American Center (2022-current). As a faculty member of the Graduate School of Agriculture, she leads the laboratory of Tropical Forest Resources and Environment (2013-current).  After receiving Ph.D from the University of Illinois (1992) and holding research positions at the University of Minnesota and Smithsonian Tropical Research Institute, she was a faculty member at the University of Florida (1997-2013) before moving to Kyoto University as a professor.