The development of organ preservation techniques has started since the onset of transplantation as a basis of the procedure. Today, the donor shortage is promoting the novel concept, “organ resuscitation”, to the preservation, in order to expand the donor pool to marginal or even submarginal donors such as donors after circulation death. This article reviews the history and recent development of organ resuscitation focusing on author’s own work. Aiming to clinical application, proof of concept was established first by the experiments with rodents and then, preclinical translational studies were performed in pigs that are mimicking well human anatomy and physiology as well as body size. The improvement of the clinical procedures is also studied in pigs as a reverse translational research. One good example, the use of hydrogen gas in preservation solution, was introduced here. The development of medical procedure is built upon the coordination of basic and clinical research, in other words, elaboration of translational and reverse translational researches. Research in organ resuscitation may realize the artificial construction of organs in test tubes.

The Japanese Association of Medical Sciences (JAMS) originally established in 1902 has been active for over 117 years as a self-driven academic organization with having a general meeting every four years. After World War II, the General Head Quarter conducted the consolidation of JAMS with the Japan Medical Association (JMA), which had had no academic activities before. This framework has lasted for almost 60 years since 1948. In 2006 the incorporation of the JAMS itself as a representative of Japanese academia was agreed internally and in 2011 the president of JMA accepted. Finally, a general incorporated association, the Japanese Medical Science Federation (JMSF) was established in 2014, while the name JAMS is still valid when the activity is cooperated with JMA. This day, the circumstances around medical sciences and healthcare undergo significant changes influenced by the domestic and international transformation of technology, politics, economy, and social situation. However, the mission of JMSF/JAMS, i.e., health safeguard and promotion of welfare, is unchanged. JMSF/JAMS will consolidate the development of medical science and technology and researchers will exert themselves to achieve fruitful progress with sufficient attention to ethics. This review refers to the social responsibility of JMSF/JAMS.

The 46th Annual Congress of the Japan Society for Organ Preservation and Biology in 2019 was held at Fukushima Medical Device Development Support Centre, an official validation center for development of medical devices. A unique feature of the center is capability of managing preclinical test with experimental pigs including advanced surgical procedure and long-term study. As the president of this annual congress, I requested a keynote lecture to Professor René H Tolba, Professor and Director, Institute for Laboratory Animal Science, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Germany, entitled “Translation in surgical research from bench to bedside: development of a new organ preservation machine and organ preservation solution”. He talked about his experiences of the development of novel bipolar device ‘EnSeal and organ preservation system/solution ‘ECOFLOW’ and ‘ECOSOL’, focusing on usefulness of experiments with pig models. It was a well-timed suggestion for the attending researchers in academia, industries, and regulatory agencies in Japan. Here, I present the brief summary of the lecture and hot discussion under the permission of Professor René H Tolba.
Lecture abstract and biography are available in Organ Biology 2019;26(3):260-261 https://doi.org/10.11378/organbio.26.260.

Culture techniques that can be used to generate three-dimensional tissues (also known as organoids) using human induced pluripotent stem cells or cells isolated from biopsy tissues have been developed. With this method, it has become possible to reproduce human fetal tissues or human tissues under pathological conditions. The organoid culture technique has its origins in stem cell biology and was developed as a method to reproduce the microenvironment (niche) that promotes self-renewal and differentiation of stem cells. However, these remarkable accomplishments of regenerative medicine and biology are not limited to the elucidation of the mechanisms underlying organogenesis but have also contributed to the fundamentals of new research fields such as human organ reconstruction for regenerative medicine. Furthermore, the tumor microenvironment within the tissue stroma is known to play an important role in the development and progression of cancer. The tumor microenvironment is thought to be formed through the interaction of various cancer cells and is deeply involved in the progression of cancer and resistance to treatment, but there are many unclear aspects. Because the organoid culture technique can reproduce a three-dimensional tissue composed of multiple types of cells, it is considered to be useful in the reconstitution of the tumor microenvironment. Therefore, research on cancer organoids is ongoing. In this paper, we focused on the use of organoids in current cancer research; specifically, we outlined the benefits of organoid technology with respect to the evaluation of drug sensitivity. Moreover, we discussed future prospects of drug evaluation using cancer organoids.

The early and accurate diagnosis of rejection after renal transplantation is required for the well-being of recipients. To develop minimally invasive diagnosis the wide variety of novel biomarkers has been evaluated in biofluids such as blood and urea, using metabolomics that performs simultaneous identification and quantification of hundreds of metabolites. Here, we reviewed the recent researches to explore the biomarkers applicable for the diagnosis of rejection after renal transplantation.

Molecular hydrogen (H₂) has the remarkable potential to selectively neutralize harmful reactive oxygen species, just leaving harmless H₂O. Towards its clinical application, however, there are multiple obstacles including flammability, high diffusivity/permeability, and low solubility. As a potential solution, we developed a simple ex vivo conditioning, HyFACS (Hydrogen Flush After Cold Storage), that involves injecting unsaturated hydrogen solution directly into the blood vessels of cold-stored organs just before implantation, In this review, we summarize the advantages of this simple end-ischemic preconditioning for solid organ transplantation by comparing the other H2 applications in the field of organ transplantation.

Stem cell technology and tissue engineering technology have remarkably developed in recent years. Large animal models which are similar to humans in anatomy have been preferred to mice and rats in preclinical studies to evaluate the efficacy and safety of the human call-based regenerative medical products. We successfully developed an operational immunodeficient pig model by surgical procedure combined with conventional immunosuppressive therapy. As a result, the long-term implantation study of human cell-based vascular grafts constructed by using a Bio-3D printer enabled the evaluation of the pre-clinical efficacy. This immunodeficient pig model is expected to be widely used in clinical development of regenerative medical products in the future.

The field of cell therapy in regenerative medicine has made remarkable progress, and in vitro differentiated cells are about to be used for disease therapy, but it is difficult to generate functional organs with a three-dimensional structure in vitro. On the other hand, the blastocyst complementation is a method of generating an organ in an animal body that is morphologically and functionally identical to an in vivo organ by utilizing the chimera-forming ability of pluripotent stem cells. This article described the current status and future prospects of organ generation using this blastocyst complementation method.

We recently developed novel 3D-4K fluorescent video system, which enables for us to resect abdominal organs finely as well as perform anastomoses of tiny vessels, bile ducts and pancreatic duct. The surgical field is displayed on a screen via a high-resolution (4K) 3D-camera that formerly required use of a magnifying surgical loupe. Our novel system is useful for the following points. 1.The operator and assistants have the same field of view in heads-up surgery, which indicates this system is suitable for surgical education. 2.The focal depth is not greatly disturbed by pulsing blood vessels or movement such as respiration.3. Using this system, surgeons may tolerate long operative times with “Head-up” status, which will not injure the surgeon’s neck.

Drug-drug interactions (DDI) between tacrolimus (TAC) and proton pump inhibitors (PPIs) were summarized to assess magnitude of the DDI in terms of the Cytochrome P450 (CYP) responsible for TAC and PPIs metabolism. The combined use of TAC and PPIs, omeprazole and lansoprazole, provides a DDI, that increase blood levels of TAC. Omeprazole and lansoprazole inhibit the TAC metabolism on CYP3A4, a common metabolic enzyme for both PPIs and TAC, as the estimated mechanism for DDI. It has been reported that genetic polymorphisms of CYP2C19, an another metabolic enzyme for PPIs, were associated with this DDI, where poor metabolic ability for PPIs enhanced the magnitude. On the other hand, co-administration of rabeprazole, an alternative PPIs, provides little effect on this DDI because the main metabolic pathway is non-enzymatic degradation. The information is limited whether or not vonoprazan, a novel PPIs and substrate for CYP3A4, produces DDI with TAC as well as conventional PPIs. We present a case of renal transplant recipient whose blood TAC was increased after introduction of vonoprazan, suggesting a potential DDI with TAC.

Generation of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) has been a long-standing, challenging goal of hematology. In this review, current advances toward the goal utilizing various in-vitro differentiation techniques and animal in-vivo microenvironments will be summarized. In addition, we will introduce our unique method of sheep in-utero transplantation targeting a fetal liver as an in vivo microenvironment for hematopoietic engraftment.

The severe shortage of donors is the biggest problem for Japanese transplantation. In addition to the lack of sufficient organs for patients with organ failure, this problem also makes it difficult to pass on organ procurement techniques to the next generation of transplant surgeons. We herein introduce educational tools, such as books, Internet resources, and animal lab simulations and video that can help to make up for a lack of practical experience in organ procurement. We deeply believe that these tools will be useful for the education of the next generation of transplant surgeons.

Recent progress of iPS cell technology is one of the promising avenues for organ replacement therapy. Decellularized tissue have been applied to achieve a more complex level of tissue organizations with some success in animal models. If decellularization technology can provide complex liver construction and function as well as niche for the large amount of hepatic cells to replace its metabolic utility, liver regenerative therapy will be realistic. In this review, we focus on organ decellularization as a new regenerative medicine approach, most recently for whole organs, that may be applied in the field of iPS cell therapy.

It has become clear that temperature plays a major role in many life phenomena. However, little is known about the intracellular temperature, and the relationship between regenerative function and intracellular temperature of stem cells. In this study, fluorescent nanodiamond (FND) that can be applied as an excellent quantum sensor was used for stem cell labeling. Then, the relationship between the regenerative function of stem cells and the intracellular temperature of stem cells was evaluated by a sensing the optically detected magnetic resonance (ODMR) activity of NV centers in FNDs. FNDs could label adipose tissue-derived stem cells (ASCs) at high efficiency with 24 h incubation, and no cytotoxicity was observed in ASCs labeled with less than 500 µg/mL of FNDs. The ODMR of NV centers in FNDs was confirmed at approximately 2.87 GHz with a characteristic fluorescence spectrum, and the intracellular temperature of living ASCs during several days of culturing could be precisely measured. Moreover, the intracellular temperature was found to influence the production of growth factors and the degree of differentiation into adipocytes and osteocytes. These data suggest that NV centers in FNDs can be used to investigate the relationship between intracellular temperature and cellular functions.

Machine learning is an effective tool to analyze large amount of data including medical images and clinical data. The application of machine learning to machine perfusion, a specialized preservation technique of organs for transplantation, is hoped to provide more successful outcome. Machine perfusion is a promising technology for not only preservation but also resuscitation and estimation of donor grafts, especially marginal grafts such as donors after cardiac death. The analysis of parameters obtained by perfusion will predict the graft performance and help doctors’ decision whether the organ befits transplantation or not. Organ assessment supported with machine learning may extend donor criteria and increase donor number eventually. Here, we introduce general feature of machine learning and discuss the potential of its application to flow distribution imaging evaluation for organ assessment with our results of ex vivo image analysis of liver.

In Ibaraki Prefecture, the number of brain-deaths or cardiac-death donors has been low, 1-3 cases/year, which is below the average of the all prefectures in Japan. Besides innovations in the medical systems, public inspiration to facilitate organ donation, especially to the population which has no interest, is vital in order to increase basic donation rates. From 2008, Ibaraki Kidney Foundation (IKF) has been providing a lecture called, “The Lecture of Life” to adolescents to educate them about organ donations. It is targeted to students from elementary to high school in the prefecture, and the contents of lectures are adjusted to their understanding based on age. The main purpose of this lecture is to provide opportunity to encourage students to discuss about “organ donation” and “death” with their family and friends, and make them understand the preciousness of life, which could connect to declarations of their wills for organ donations. From a research by the IKF, it was indicated that students who took this lecture felt the preciousness of life stronger and became more passionate towards organ donations. In addition, it could inspire organ donations from their parents who had no interests. Over the past 11 years, IKF has been providing the lecture to over 14,000 students. Through this lecture, the students could become future donors, and their parents to be the current donors by the inspiration received from their children. It was found that the declaration of the will for organ donations amongst the public in Ibaraki Prefecture in 2015 was higher than the average of other prefectures. Furthermore, along with innovations in medical systems, the donation rate has dramatically increased in 2019. The IKF plans to continue to provide this lecture to the students and the public as initiatives to promote organ donations.

Protective effects of quercetin (QE) on cold injury of liver were investigated with the preservation experiments of isolated hepatocytes and whole liver in rats. When hepatocytes were stored at 4°C for 1 day, the viable cells decreased to 3.7% and 5.7% in saline and commercial hepatocyte incubation medium, respectively. The addition of 3.3 and 33.1 μmol/L of QE significantly improved the cell viability to 28.3 and 23.7%, respectively (p<0.05). In liver cold storage model, the addition of QE suppressed the leakage of alanine aminotransferase in the preservation solution. Interestingly, sucrose enhanced the effect of QE. When the preserved livers were transplanted orthotopically, the addition of QE and sucrose to the UW solution decreased serum aminotransferase levels significantly compared with UW solution alone and the levels were almost the same as those of non-preserved fresh graft group. Our findings suggest that addition of QE and sucrose to UW solution can improve liver preservation and the outcomes of liver transplantation.

Unprecedented pandemic of COVID-19 is threatening the world in 2020. Most emergent viruses have originated from zoonosis. As an expert in the use of pigs for medical research and training where pigs are often urged to accept human tissue/cells/organs, the perspective of coping with zoonosis are reviewed from the different view from livestock science.