View source for Organ Fabrication Using Pigs as An in Vivo Bioreactor

Organ transplantation is often the only possible treatment for a patient when an old worn-out organ fails. The organs are donated from either living or deceased donors, and thus the number of transplantable organs is limited and insufficient to meet the clinical demand.  It is especially difficult if a young and healthy organ is required.

The discovery of the potential of induced pluripotent stem cells (iPSCs), to regenerate tissues or organs offers new hope to overcome this situation.<ref>Milhavet, O., & Lemaitre, J. M. (2014). Senescent-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. Tumor Dormancy, Quiescence, and Senescence, Volume 2: Aging, Cancer, and Noncancer Pathologies, 265-276. https://doi.org/10.1007/978-94-007-7726-2_25</ref><ref>Lee, J., Bignone, P. A., Coles, L. S., Liu, Y., Snyder, E., & Larocca, D. (2020). Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells. Biochemical and Biophysical Research Communications, 525(3), 563-569.  https://doi.org/10.1016/j.bbrc.2020.02.092</ref> Human iPSCs are now widely used to generate young tissues or organs, and techniques for the in vitro production of specific cell types have been developed.<ref name="Baghbaderani">Babu, S. S., Duvvuru, H., Baker, J., Switalski, S., Shafa, M., Panchalingam, K. M., ... & Baghbaderani, B. A. (2023). Characterization of human induced pluripotent stems cells: Current approaches, challenges, and future solutions. Biotechnology Reports, e00784. PMID: 36818379 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929203/ PMC9929203] DOI: 10.1016/j.btre.2023.e00784</ref><ref>Wang, J., Sun, S., & Deng, H. (2023). Chemical reprogramming for cell fate manipulation: Methods, applications, and perspectives. Cell Stem Cell, 30(9), 1130-1147. PMID: 37625410 DOI: 10.1016/j.stem.2023.08.001</ref>  However, these strategies still have several limitations for clinical application, including the size, maturity, function, and risk of tumor formation after transplantation.<ref name="Baghbaderani"/>

Pigs are very similar to humans in body size and in the structure, metabolism of the internal organs and in embryonic development. For this reason, pig is an animal attracting attention as a human disease and xenotransplantation model.<ref>Reardon, S. (2022). Will pigs solve the organ crisis? The future of animal-to-human transplants. Nature, 611(7937), 654-656. https://doi.org/10.1038/d41586-022-03794-2</ref> 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.<ref>Kobayashi, E., Tohyama, S., & Fukuda, K. (2020). Organ fabrication using pigs as an in vivo bioreactor. The Keio Journal of Medicine, 69(2), 30-36. https://doi.org/10.2302/kjm.2019-0006-OA</ref><ref>Kawai, Y., Tohyama, S., Shimizu, H., Fukuda, K., & Kobayashi, E. (2019). Pigs as Models of Preclinical Studies and In Vivo Bioreactors for Generation of Human Organs. IntechOpen.DOI: 10.5772/intechopen.90202</ref> 

One method for obtaining a transgenic multicellular organism is to transform cells in culture and inject them into an early developmental stage, thereby creating an embryo that is a mixture of original cells and transgenic cells. If any of the transgenic cells give rise to gametes in the adult animal, the resulting zygotes will have the transgene and will develop into offspring that have the transgene in all of their cells.

'''Subsequently, severe combined immunodeficient (SCID)''' pigs were developed  by serial nuclear transfer using fibroblasts with disruption of the X-linked interleukin 2 receptor subunit gamma (''IL2RG'') gene, as this mutation is known to cause X-linked SCID in humans. The SCID pigs accepted human cells, indicating their potential in preclinical studies.  However, raising these pigs is a technical challenge; among the 31 cloned piglets produced, only four survived for over 1 year. In addition, SCID pigs must be raised under meticulous hygiene conditions, which impose a further cost for their establishment and maintenance. Therefore, it is not practical to use SCID pigs as models in preclinical studies and in vivo reactors.<ref>Chen, P. R., Uh, K., Redel, B. K., Reese, E. D., Prather, R. S., & Lee, K. (2022). Production of pigs from porcine embryos generated in vitro. Frontiers in Animal Science, 3, 826324. https://doi.org/10.3389/fanim.2022.826324</ref>

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