Successful organ transplantation has been performed in parallel with the development of several immunosuppressive drugs. It is also important to carry out personalized immunosuppressive therapy to improve clinical outcome of organ transplantation. Clinical-pharmacological approaches have given many valuable insights into effective and safe drug use in organ transplantations. Here we summarize our clinical approaches concerning the personalized immunosuppressive therapy in renal transplantation by utilizing the data for individual peripheral-lymphocyte sensitivity to the immunosuppressive drugs. We also introduce, in this review, our pharmaceutical approach to improve organ preservation efficacy of the standard UW solution by adding new drugs or components to the solution.

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Main points of ISSCR (The International Society for Stem Cell Research)’s amended guidelines of 2016 were summarized. The guidelines are presented as a single document based on the preceding two ISSCR guidelines, with a preamble that articulates core ethical principles for guiding both basic and clinical stem cell research: the integrity of the research enterprise, the primacy of patient welfare, respect for research subjects, transparency, and social justice. As they concern irreproducible results and the incomplete reporting of findings from preclinical studies, they strongly require rigorous demonstration of preclinical evidence and rigorous peer review of clinical trial protocols and study reporting.

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We have previously reported that the differentiation of xeno-carbohydrate antigen-reactive B-1b cells is resistant to the effect of calcineurin inhibitors. Recent reports have indicated that the intrinsic B-cell MyD88 signaling plays an important role in T cell-independent antibody responses and in differentiation of antibody-secreting cells. In this study, we demonstrated that blocking TLR-MyD88 signaling enhanced the effect of calcineurin inhibitors on B-1b cells, both in vitro and in vivo. Therefore, TLR-MyD88 signaling can be a therapeutic target in managing the xeno-carbohydrate antigen-reactive B cell response.

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Lung transplantation (LTx) has become the mainstay for treatment of end-stage respiratory diseases. However postoperative 90-day mortality rate is 11% according to the international registry data and 5.4% in Japan. The most major cause of early death after LTx is primary graft dysfunction (PGD) mainly due to ischemia-reperfusion lung injury. Ischemia-reperfusion of the lung has been shown to induce overproduction of reactive oxygen species, which leads to the progression of severe lung injury and pulmonary edema. Nrf2 is a key transcription factor that activates many antioxidant enzymes. To test whether Nrf2 protects lungs from ischemia-reperfusion injury, wild-type (WT) rats underwent left LTx from Nrf2 knockout (KO) or WT rats, and pulmonary injury and edema were compared. Lung grafts from Nrf2 KO rats showed more pulmonary edema and reduced lung compliance when compared with those from WT rats. Pretreatment of the recipient rats with Nrf2 activator oltipraz attenuated ischemia-reperfusion-induced edema in the grafts from WT rats, but not in the grafts from Nrf2 KO rats. These results indicate that Nrf2 plays a role in protection against ischemia-reperfusion injury and that Nrf2 activators have a therapeutic potency for the prevention of PGD after LTx.

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Liver transplantation has become a well-established treatment for patients with end-stage liver disease. However, cold ischemia/warm reperfusion (CI/WR) injury remains a major cause of primary dysfunction of liver grafts and its mechanism is still poorly understood. Here, using prolonged CI and orthotopic transplantation of rat liver grafts, we found that the CI/WR injury was closely associated with autophagic pathway. Moreover, we also showed that the inhibition of autophagy reduced both liver damage and the mortality rate of recipient rats. The protective effects of suppressing autophagic pathway may suggest new strategy to prevent CI/WR injury of the liver.

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The number of deceased donors including donors after cardiac arrest tends to decrease in Japan, while the number of donors after brain death has increased since the revision of the Organ Transplant Law. Nevertheless, the number of donor organs has increased and cadaveric transplantation has penetrated the public’s awareness. Organ transplantation should be built upon cadaveric donors, and only the increase of the donor organs will lead a decrease of the number of waiting patients. The statistical mode value in organ donation after brain death was one case per year in Class 5 hospitals. It is expected that the number of organ donation after cardiac arrest may further decrease in the future. Effective utilization of staff, space, and resources can be achieved by introducing the motto, “One keep one share”. The rational and smooth organ transplantation medical care will improve the overall process of transplantation. Ideally, each transplantation institution promotes “One transplantation, one donation” to increase the number of cadaveric organ donation, which is exactly the “Baton of transplantation, and baton of life”.

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Recently, the use of percutaneous cardiopulmonary support (PCPS) for patients with heart failure, such as those with acute myocardial infarction or lethal cardiac arrhythmia, is increasing. And non-heart-beating-donor (NHBD) who have been treated with PCPS is also increasing. In this study, we reported a kidney transplantation from NHBD using PCPS at our center. Considering that our patient discharged with good kidney condition, this procedure may expand the donor pool.

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Extensive efforts to repair the extended criteria donor (ECD) grafts by machine perfusion has been reported. Although the optimal conditions, such as the perfusate, temperature, time, and the device, has not yet been established, organ perfusion is generally accepted as a promising concept. Here, we review current progress of antioxidant and anti-inflammatory treatment by induction of protective transcription factors (TFs), Nrf2 in relation to the other TFs (AP-1 and NF-kB). These TFs are mainly regulated by the redox status of intracellular thiols. Possible interactions of the TFs and the methods to regulate their activity have been described.

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Although clinical research of islet transplantation for type 1 diabetes has started in Japan, severe donor shortage hampers the progress. A possible solution is use of marginal donors such as donors after cardiac death (DCD). A continuous hypothermic perfusion machine, LifePort^TM (LP) has been developed and supplied by Organ Recovery Systems, Inc. and used for preservation and transportation of marginal kidney for organ transplantation. The effectiveness has been approved especially in the preservation. We applied LP to preservation of pancreas that is sensitive to ischemia reperfusion injury and found that the machine would be efficacious on islet isolation. [Method] Beagle dog pancreas was subjected to warm ischemic injury for 30min and preserved for 24hr by following three methods; continuous hypothermic perfusion by LP (LP group), simple cold storage in UW solution (UW group), two-layer method (TL group). Then, islets were isolated. [Results] Morphologically, large good quality islets were obtained in LP group. The larger amount of purified islet was recovered in LP group than UW and TL groups. In addition, when insulin secretion activities were estimated by static incubation, islets of LP group were the most functional among all. [Conclusion] In experimental DCD pancreas model, continuous hypothermic machine perfusion resulted in higher recovery and function of islets than simple cold storage and two layer method. Further improvement will achieve clinical application of the method on DCD pancreas preservation.

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Due to worldwide critical shortage of donor organs, extended-criteria donors (ECD) have been attracting much attention for organ transplantation. Here we describe brief summary of various strategies to utilize ECD organs, and introduce our recent research progresses targeting for functional restoration or maintenance of ECD livers.

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While outcome after organ transplantation are dramatically improving, insufficient organs available for transplant has been a worldwide problem. To resolve this issue, attempts to enable transplantation of organs from donors who have failed into cardiac arrest has gained momentum in nations with advanced transplantation procedures. Perfusion (cultivation) storage of extracted organs is gaining attention as a novel technology that has made the biggest contribution to these attempts. This general outline describes the background before the author newly introduces the developed technology of stitching blood vessels while perfusing transplanted organs. In the past, transplanted organs were in the worst warm ischemic state when placed in the recipient until the blood vessels were connected. However, using this method maintains the perfusion state, allowing control of organ temperature and oxygen supply. The author also introduced a new heat insulation sheet for wrapping the transplanted organs during transplant to improve this technology further. I believe these technologies will greatly contribute to the success of transplantation of cardiac arrest organs as well as artificially regenerated organs.

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In this review, the progress and development of regenerative medicine, therapy with cultured cells is shown. We have developed temperature-responsive culture dishes. Since a temperature-responsive polymer, poly (N-isopropylacrylamide) is covalently immobilized on the surfaces, upon temperature reduction below 32°C without need for any proteolytic enzyme, cultured cells are noninvasively harvested as a contiguous cell sheets together with the own extracellular matrix deposited during culture beneath the cell sheets. In particular, clinical applications of cell sheet-based regenerative medicine in various fields that we have performed were focused on.

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Quantum dots (QDs) have excellent fluorescence properties in comparison to traditional fluorescence probes. Thus, the optical application of QDs is in rapid expansion to each field of analytical chemistry. In this paper, we described about the application of QDs to regenerative medicine, especially stem cell transplantation therapy. Specifically, labeling technologies of stem cells by QDs composed of semiconductor materials in combination with poly-cationic liposome (Lipofectamine^®) or cell penetrating peptide (octa-arginine) were reviewed. Moreover, in vivo imaging of transplanted stem cells in mice by QDs emitting fluorescence in near-infrared region, which could be detected by fluorescence in vivo imaging machines such as IVIS imaging system, was reported.

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To develop an effective organ/cell preservation method and to monitor post-transplant graft function continuously and non-invasively, an innovative optic technology to visualize cell/organ function seems to be useful. We have developed some optic probes to visualize regulated cell death (apoptosis, necroptosis, pyroptosis), redox states and cellular stresses, pH and cellular antigens in deeper lesions of the organ. In the hepatic ischemia/reperfusion model of mice, we successfully imaged liver oxidative stress (by redox-sensitive GFP) and apoptosis (by caspase-3 activity) non-invasively and chronologically in a single mouse. We also developed a unique tool to visualize intracellular pH and succeeded in imaging dynamic changes of pH in a mouse posterior limb ischemia/reperfusion model. We are also developing the new devices for tissue/organ imaging. We are trying to monitor the optic signals chronologically and track the lesions in the body by developing light sensor and multiple CCD camera system, which can be used in endoscopic examination and surgical operation. It is still on a way, but this kind of technology will definitely provide a new avenue toward effective and non-invasive surgical therapy in the future.

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The pancreatic islet is a functional unit of the pancreatic endocrine system, and it has a potential to cure type 1 diabetes by transplantation. However, donor shortage is a serious problem. To solve this, it is suggested to use the islet-like tissues from pancreatic beta cell lines or iPS cell derived insulin-producing cells. In this paper, we introduce a three-dimensional culture method for constructing islet-like tissues with microstructures those can enhance the insulin secretion activity. The islet-like tissues showed higher insulin secretion activity by mixing α cells and/or hydrogel beads. Moreover, the islet-like tissues containing pancreatic alpha cells exhibited higher therapeutic performance when they were transplanted under the kidney capsules of the streptozotocin-induced diabetic mice. Achievement to develop more functional islet-like tissues results in a reduction of medical cost as well as cell number in transplantation. The concept of redesigning the microstructure of islet-like tissues may be effective for future transplantation treatment.

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The only way to settle the problem of the lack of donor organs for organ transplantation is to produce the organ alternatives by biomedical engineering. Thus, we started to challenge an innovative approach of additive organ manufacturing where cells are arranged and piled up, and tissues and organs are constructed. 1) make capillary by bio-patterning! 2) develop a 3D bioprinting machine with which 3D structures can be constructed with cells! and 3) develop a processing line with which an organ can be constructed! We would like to carry on in these challenges to provide and deliver organs to the patients waiting for donor organs.

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