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REVIEW Organ Fabrication Using Pigs As an in Vivo Bioreactor REVIEW Organ Fabrication Using Pigs as An in Vivo Bioreactor Eiji Kobayashi,1 Shugo Tohyama1,2 and Keiichi Fukuda2 1Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan 2Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (Received for publication on May 23, 2019) (Revised for publication on July 15, 2019) (Accepted for publication on July 17, 2019) (Published online in advance on August 6, 2019) We present the most recent research results on the creation of pigs that can accept human cells. Pigs in which grafted human cells can flourish are essential for studies of the production of human organs in the pig and for verification of the efficacy of cells and tissues of human origin for use in regenerative therapy. First, against the background of a worldwide shortage of donor organs, the need for future medical technology to produce human organs for transplantation is discussed. We then describe proof- of-concept studies in small animals used to produce human organs. An overview of the history of studies examining the induction of immune tolerance by techniques involving fertilized animal eggs and the injection of human cells into fetuses or neonatal animals is also presented. Finally, current and future prospects for producing pigs that can accept human cells and tissues for experimental purposes are discussed. (DOI: 10.2302/kjm.2019-0006-OA; Keio J Med 69 (2) : 30–36, June 2020) Keywords: organ fabrication, donor shortage, in vivo bioreactor, pig, stem cell Introduction nor and has saved many lives. However, there is a great demand for next-generation medical treatments to render Organ transplantation has become well established as organ transplantation unnecessary, e.g., promotion of the “the wonder treatment” of the 20th century as a final concept of the production of “transplantable organs” in treatment for patients with organ failure and no other hope patients themselves and research and development of spe- for survival.1 While the prognosis for transplant patients cific techniques to this end.4 has dramatically improved, there is a chronic worldwide Much progress has been made in recent years in the fun- shortage of donor organs. This profound shortage of or- damental research of stem cells. Techniques for the test- gans has encouraged the unethical or illegal sourcing of tube production of organs from pluripotent cells can be donors. In an early initiative of the 2008 Istanbul Dec- applied to humans. Human embryonic stem cells (ESCs)5 laration, professionals engaged in organ transplantation and human induced pluripotent stem cells (iPSCs)6 have demanded the following guarantees: (1) opposition to or- been produced as human pluripotent stem cells. These gan trafficking and transplant commercialism, (2) promo- achievements are promising for research into the produc- tion of transplantation from deceased donors in the same tion of vital organs in the laboratory. One current issue is country and/or region, and (3) protection and following the need for reactors that provide the infrastructure for or- up of living donors.2 Various efforts have been made in gan development and also supply oxygen and nutrition for many countries, but 10 years later, the organ shortage has the continued production and growth of organs. The pig not improved. E.K., one of the authors, has participated has been identified as the animal most likely to provide in living donor liver transplantation in clinical practice the required in vivo reactor infrastructure. As the next in Japan.3 Living donor transplantation was developed step, pigs that can accept human cells and tissues must be as the sole alternative in the absence of a deceased do- produced. To achieve this, techniques for suppressing im- Reprint requests to: Eiji Kobayashi, MD, PhD, Department of Organ Fabrication, Keio University School of Medicine, 35 Shinanomachi, Shin- juku-ku, Tokyo 160-8582, Japan, Email: [email protected] Copyright © 2019 by The Keio Journal of Medicine 30 Keio J Med 2020; 69 (2): 30–36 31 munity in the pig to enable acceptance of human cells and rat pancreatic islets of Langerhans. Islets of Langerhans for inducing immune tolerance to cells must be evaluat- taken from the mouse pancreas produced an effect when ed. Immunosuppression has been successful in pigs7–11; transplanted into diabetes-induced rats.14 For this strat- however, unlike for small animals, management of the egy, apancreatic pig that did not develop a pancreas have rearing of these immunocompromised pigs makes organ also been successfully produced, and it has been dem- production scientifically and economically difficult.12 onstrated that after blastocyst exchange with a healthy In this review, we first provide an overview of recent pig, a pancreas is formed from the exogenous cells as studies on the production of human tissues and organs the apancreatic pig could not survive for a long time.15 in living pigs. After describing studies related to im- This technique produces xenogenic chimera at the level mune tolerance (which involves elimination of immune of the fetus, and animals capable of development can responses in individual animals), we introduce recent re- grow with normal immunocompetence. In recent years, search on the production of pigs that can accept human the production of pig–human chimera at the fetal level cells and tissues. was also performed at the Salk Institute (USA).16 They showed that human ESCs or iPSCs could be introduced Proof of Concept in Small Animals of Techniques for into fertilized pig eggs to produce a human–pig chimera. Growing Human Organs in Pigs However, this technique raises serious ethical questions. Consequently, there are limitations to creating a chimera The technology used for producing antibodies or drugs with a mixture of pig and human cells that are introduced to be used in humans and for producing cells and/or tis- at the fetal level. For human–pig chimeras, it has been sues of human origin in the bodies of living animals are said that “such a horrible creature should not be brought referred to as “animal factories” or in vivo bioreactors. to term.” Moreover, the introduction of heterologous cells Pigs have attracted much attention in this respect: in ad- and genes during insemination must be thoroughly con- dition to the history and social importance of the hygienic sidered, not only from the perspective of legal problems management of the pig as a food animal, in recent years regarding the insemination procedure, but also for the it has also been evaluated for developmental engineer- loss of the personal identity of a living being. To better ing purposes. It is an additional advantage that they give understand the production of the human-pig xenogenic birth to multiple offspring from the economical and ethi- chimera, we summarize these approaches for human cell cal points of view. injection into the pig in Fig. 1. In studies of transplantation between mice and rats, Overcoming the ethical issue of xeno-chimera, the we successfully replaced, in vivo, the livers of mice with methods for inducing immune tolerance by injecting hu- rat hepatocytes, which were then transplanted into rats.13 man cells into pig fetuses have been reconsidered. Numer- Rat hepatocytes were injected into severe combined im- ous studies have examined heterogeneic cell transplanta- munodeficient (SCID) mouse pups. For use as an in vivo tion. Experiments inducing immune tolerance within the bioreactor, the mice were subjected to genetic procedures same species are free from the ethical and legal problems that caused progressive damage to the liver, preventing described above. This history of the concept of immune its development. As the SCID mice grew, the livers were tolerance is reviewed in the next section. replaced with rat hepatocytes. In the livers of mice pro- duced using this technique, more than 95% of cells were Historical Background of Immune Tolerance replaced with rat hepatocytes. Although the vascular system and biliary system were still murine, when such Medawer, who together with Burnet, won the Nobel livers were transplanted with blood vessels attached into Prize in 1960 for Physiology and Medicine, reviewed the the rat as a recipient, the recipient rat were extremely im- progress of immunological tolerance at the time.17 Medaw- munologically viable and showed long-term survival.13 er first described the work of Owen in 1945. Owen in- However, the mice as in vivo reactors must be SCID to vestigated more than 80 pairs of twin calves, nearly all accept injected xenogenic rat cells. Evidently, SCID pigs of which had the same blood type,18 and discovered that would be required to verify this principle in human-sized individual calves that experience anastomosis in the pla- pigs. However, the extremely high costs of reproduction centa accepted the exchange of skin grafts after maturity. and hygiene management of SCID pigs is a considerable In multiple fetuses of different sexes, female fetuses, in limitation to the future development of this approach. which there is abnormal differentiation of the reproduc- Nakauchi et al. have established a developmental engi- tive organs causing infertility, are called freemartins and neering method for heterogeneic mouse–rat transplanta- are the result of blood chimerism produced by placental tion of the pancreas in which the target organ increased14). anastomosis. The sex chromosomes show XX/XY chi- In this technique, a key gene associated with organ devel- merism, which is thought to exist at 1–2% in the Holstein opment in the mouse is knocked out and, after fertiliza- breed. tion, the blastocyst of knocked out mice is complemented In 1950, Hasek reported that this phenomenon could with rat iPSCs. Mice born using this procedure contain be reproduced experimentally in different species. He 32 Kobayashi, E, et al: Production of Pigs That Can Accept Human Cells Fig.
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