Techniques of orthotopic renal transplantation. II. Size-matched porcine grafts in monkey recipients

Takamura, Tsuyoshi; Sasaki, Hiroshi; Hirayama, Haruyuki; Kiyoshi, Akihiko; Matsui, Kenji; Matsumoto, Naoto; Saito, Yatsumu; Fujimoto, Toshinari; Tajiri, Susumu; Yamanaka, Shuichiro; Matsumoto, Keīichi; Miyawaki, Toshio; Yokoo, Takashi; Kobayashi, Eiji

doi:10.1590/acb360503

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…For fetal kidney transplantation, we have shown that the periaortic region is superior for development in a small animal model of rats ( 23 ). In preclinical xenotransplantation of adult kidneys from pigs to monkeys, we have shown that orthotopic transplantation is superior ( 24 ). For the transplantation of renal organoids, we have previously developed a simple method of transplanting them under the renal membrane without damage ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

Beneficial Impact of Interspecies Chimeric Renal Organoids Against a Xenogeneic Immune Response

et al. 2022

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BackgroundAnimal fetal kidneys have the potential to be used as scaffolds for organ regeneration. We generated interspecies chimeric renal organoids by adding heterologous rat renal progenitor cells to single cells from mouse fetal kidneys and applying the renal development mechanism of mouse fetuses to rat renal progenitor cells to examine whether rat renal progenitor cells can differentiate into renal tissues of the three progenitor cell lineages of kidneys between different species. Furthermore, we investigated whether chimeric renal organoids with an increased proportion of recipient cells reduce xenogeneic rejection.MethodsC57BL/6JJmsSlc mice (B6 mice) and Sprague-Dawley-Tg (CAG-EGFP) rat (GFP rats) fetuses were used as donors, and mature male NOD/Shi-scid, IL-2RγKO Jic mice (NOG mice) and Sprague-Dawley rats (SD rats) were used as recipients. First, fetal kidneys were removed from E13.5 B6 mice or E15.5 GFP rats and enzymatically dissociated into single cells. These cells were then mixed in equal proportions to produce chimeric renal organoids in vitro. The chimeric organoids were transplanted under the renal capsule of NOG mice, and maturation of the renal tissues in the organoids was observed histologically. Furthermore, chimeric organoids were prepared by changing the ratio of cells derived from mouse and rat fetal kidneys and transplanted under the renal capsule of SD rats subjected to mild immunosuppression to pathologically analyze the strength of the xenogeneic immune response.ResultsThe cap mesenchyme was reconstructed in vitro, and nephron progenitor cells and ureteric buds were mosaically comprised GFP-negative mouse and GFP-positive rat cells. In the in vivo environment of immunodeficient mice, chimeric renal organoids mosaically differentiated and matured into renal tissues of three lineages. Chimeric renal organoids with high rates of recipient rat cells showed milder rejection than complete xenograft organoids. The vessels of recipient rats entered from the periphery of the transplanted chimeric renal organoids, which might reduce their immunogenicity.ConclusionInterspecies chimeric renal organoids may differentiate into mature renal tissues of each renal progenitor cell lineage. Furthermore, they may reduce transplant rejection compared with xenograft organoids.

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Section: Discussionmentioning

confidence: 99%

Beneficial Impact of Interspecies Chimeric Renal Organoids Against a Xenogeneic Immune Response

et al. 2022

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“…However, unlike tissue transplantation, the reaggregates are extremely fragile, and it was necessary to devise a transplantation method. In previous studies, we have reported the convenience of orthotopic transplantation 14 , 15 . The method we developed in the previous study was also selected for orthotopic transplantation under the renal capsule, but we established a method to detach the capsule, create a pocket space, and transplant the fragile organoids under water pressure control.…”

Section: Discussionmentioning

confidence: 99%

Techniques of fragile renal organoids transplantation in mice

et al. 2021

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Purpose: This study aimed to develop a microsurgical technique to transplant extremely fragile renal organoids in vivo , created by in-vitro reaggregation of metanephros from fetal mice. These organoids in reaggregation and development were examined histologically after transplantation under the renal capsule. Methods: Initially, metanephros from fetal mice were enzymatically treated to form single cells, and spheroids were generated in vitro . Under a microscope, the renal capsule was detached to avoid bleeding, and the outer cylinder of the indwelling needle was inserted to detach the renal parenchyma from the renal capsule using water pressure. The reaggregated spheroid was aspirated from the culture plate using a syringe with an indwelling needle outer cylinder and carefully extruded under the capsule. Pathological analysis was performed to evaluate changes in reaggregated spheroids over time and the effects of co-culture of spinal cord and subcapsular implantation on maturation. Results: In vitro , the formation of luminal structures became clearer on day 5. These fragile organoids were successfully implanted without tissue crapes under the renal capsule and formed glomerular. The effect of spinal cord co-transplant was not obvious histrionically. Conclusions: A simple and easy method to transplant fragile spheroids and renal under the renal capsule without damage was developed.

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“…Many other preclinical trials transplanting pig hearts, kidneys, islet cells, and cornea have been performed using effective immunosuppression regimens [27,63,[108][109][110][111][112]. Unfortunately, in these studies, PERV transmission was not analyzed, but at least no clinical signs of a retrovirus infection were observed.…”

Section: Rhesus Monkeysmentioning

confidence: 99%

Porcine Endogenous Retroviruses and Xenotransplantation, 2021

Denner

2021

Viruses

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Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for xenotransplantation, the transplantation of pig cells, tissues, or organ to humans in order to alleviate the shortage of human donor organs. Up to 2021, a huge body of knowledge about PERVs has been accumulated regarding their biology, including replication, recombination, origin, host range, and immunosuppressive properties. Until now, no PERV transmission has been observed in clinical trials transplanting pig islet cells into diabetic humans, in preclinical trials transplanting pig cells and organs into nonhuman primates with remarkable long survival times of the transplant, and in infection experiments with several animal species. Nevertheless, in order to prevent virus transmission to the recipient, numerous strategies have been developed, including selection of PERV-C-free animals, RNA interference, antiviral drugs, vaccination, and genome editing. Furthermore, at present there are no more experimental approaches to evaluate the full risk until we move to the clinic.

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Techniques of orthotopic renal transplantation. II. Size-matched porcine grafts in monkey recipients

Cited by 4 publications

References 14 publications

Beneficial Impact of Interspecies Chimeric Renal Organoids Against a Xenogeneic Immune Response

Beneficial Impact of Interspecies Chimeric Renal Organoids Against a Xenogeneic Immune Response

Techniques of fragile renal organoids transplantation in mice

Porcine Endogenous Retroviruses and Xenotransplantation, 2021

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