Generation of Human-pig Chimeric Renal Organoids Using IPSC Technology

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Oct 7

PMID 39375428

Authors

Koki Fujimori

Shuichiro Yamanaka

Kentaro Shimada

Kenji Matsui

Shiho Kawagoe

Takao Kuroda

Atsushi Ikeda

Makoto Inoue

Eiji Kobayashi

Takashi Yokoo

Affiliations

Soon will be listed here.

Abstract

Porcine organs and human induced pluripotent stem cell (iPSC)-derived organoids as alternative organs for human transplantation have garnered attention, but both face technical challenges. Interspecies chimeric organ production using human iPSCs shows promise in overcoming these challenges. Our group successfully generated chimeric renal organoids using human iPSC-derived nephron progenitor cells (NPCs) and fetal mouse kidneys. However, the current technology is limited to rodents. Therefore, this study focused on producing human-pig chimeric renal organoids, as pigs are the most promising species for xenotransplantation. Modification of existing culture systems enables continuous renal development in both species, resulting in the successful creation of human-pig chimeric renal organoids. Moreover, this method can be applied to generate humanized xenogeneic kidneys for future clinical applications. This study provides evidence that optimizing culture conditions enables the early-stage kidney development beyond species barriers, thus laying the foundation for accelerating research on humanized xenogeneic kidney fabrication for clinical purposes.

References

Low J, Li P, Chew E, Zhou B, Suzuki K, Zhang T . Generation of Human PSC-Derived Kidney Organoids with Patterned Nephron Segments and a De Novo Vascular Network. Cell Stem Cell. 2019; 25(3):373-387.e9. PMC: 6731150. DOI: 10.1016/j.stem.2019.06.009. View

Poladia D, Kish K, Kutay B, Hains D, Kegg H, Zhao H . Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol. 2006; 291(2):325-39. DOI: 10.1016/j.ydbio.2005.12.034. View

Taguchi A, Nishinakamura R . Higher-Order Kidney Organogenesis from Pluripotent Stem Cells. Cell Stem Cell. 2017; 21(6):730-746.e6. DOI: 10.1016/j.stem.2017.10.011. View

Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M . Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell. 2010; 142(5):787-99. DOI: 10.1016/j.cell.2010.07.039. View

Davies J, Holland I, Gul H . Kidney organoids: steps towards better organization and function. Biochem Soc Trans. 2024; 52(4):1861-1871. PMC: 11668298. DOI: 10.1042/BST20231554. View

Thomas J, Zimmerlin L, Huo J, Considine M, Cope L, Zambidis E . Running the full human developmental clock in interspecies chimeras using alternative human stem cells with expanded embryonic potential. NPJ Regen Med. 2021; 6(1):25. PMC: 8128894. DOI: 10.1038/s41536-021-00135-1. View

Montgomery R, Stern J, Lonze B, Tatapudi V, Mangiola M, Wu M . Results of Two Cases of Pig-to-Human Kidney Xenotransplantation. N Engl J Med. 2022; 386(20):1889-1898. DOI: 10.1056/NEJMoa2120238. View

Tanigawa S, Naganuma H, Kaku Y, Era T, Sakuma T, Yamamoto T . Activin Is Superior to BMP7 for Efficient Maintenance of Human iPSC-Derived Nephron Progenitors. Stem Cell Reports. 2019; 13(2):322-337. PMC: 6700502. DOI: 10.1016/j.stemcr.2019.07.003. View

Chen S, Brunskill E, Potter S, Dexheimer P, Salomonis N, Aronow B . Intrinsic Age-Dependent Changes and Cell-Cell Contacts Regulate Nephron Progenitor Lifespan. Dev Cell. 2015; 35(1):49-62. PMC: 4615609. DOI: 10.1016/j.devcel.2015.09.009. View

10.

Saito Y, Matsumoto N, Yamanaka S, Yokoo T, Kobayashi E . Beneficial Impact of Interspecies Chimeric Renal Organoids Against a Xenogeneic Immune Response. Front Immunol. 2022; 13:848433. PMC: 8885510. DOI: 10.3389/fimmu.2022.848433. View

11.

Cardoso-Moreira M, Halbert J, Valloton D, Velten B, Chen C, Shao Y . Gene expression across mammalian organ development. Nature. 2019; 571(7766):505-509. PMC: 6658352. DOI: 10.1038/s41586-019-1338-5. View

12.

Goto T, Hara H, Sanbo M, Masaki H, Sato H, Yamaguchi T . Generation of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats. Nat Commun. 2019; 10(1):451. PMC: 6363802. DOI: 10.1038/s41467-019-08394-9. View

13.

Loupy A, Goutaudier V, Giarraputo A, Mezine F, Morgand E, Robin B . Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study. Lancet. 2023; 402(10408):1158-1169. DOI: 10.1016/S0140-6736(23)01349-1. View

14.

Tan T, Wu J, Si C, Dai S, Zhang Y, Sun N . Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo. Cell. 2021; 184(8):2020-2032.e14. DOI: 10.1016/j.cell.2021.03.020. View

15.

Taguchi A, Kaku Y, Ohmori T, Sharmin S, Ogawa M, Sasaki H . Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell. 2013; 14(1):53-67. DOI: 10.1016/j.stem.2013.11.010. View

16.

Jensen K, Little M . Organoids are not organs: Sources of variation and misinformation in organoid biology. Stem Cell Reports. 2023; 18(6):1255-1270. PMC: 10277837. DOI: 10.1016/j.stemcr.2023.05.009. View

17.

Takasato M, Er P, Chiu H, Maier B, Baillie G, Ferguson C . Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2015; 526(7574):564-8. DOI: 10.1038/nature15695. View

18.

Matsui K, Yamanaka S, Chen S, Matsumoto N, Morimoto K, Kinoshita Y . Long-term viable chimeric nephrons generated from progenitor cells are a reliable model in cisplatin-induced toxicity. Commun Biol. 2023; 6(1):1097. PMC: 10613230. DOI: 10.1038/s42003-023-05484-9. View

19.

Sharmin S, Taguchi A, Kaku Y, Yoshimura Y, Ohmori T, Sakuma T . Human Induced Pluripotent Stem Cell-Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation. J Am Soc Nephrol. 2015; 27(6):1778-91. PMC: 4884101. DOI: 10.1681/ASN.2015010096. View

20.

Barak H, Huh S, Chen S, Jeanpierre C, Martinovic J, Parisot M . FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012; 22(6):1191-207. PMC: 3376351. DOI: 10.1016/j.devcel.2012.04.018. View