Interspecies Chimerism with Mammalian Pluripotent Stem Cells

• Published in: Cell Vol. 168; no. 3; pp. 473 - 486.e15
• Main Authors: Wu, Jun, Platero-Luengo, Aida, Sakurai, Masahiro, Sugawara, Atsushi, Gil, Maria Antonia, Yamauchi, Takayoshi, Suzuki, Keiichiro, Bogliotti, Yanina Soledad, Cuello, Cristina, Morales Valencia, Mariana, Okumura, Daiji, Luo, Jingping, Vilariño, Marcela, Parrilla, Inmaculada, Soto, Delia Alba, Martinez, Cristina A., Hishida, Tomoaki, Sánchez-Bautista, Sonia, Martinez-Martinez, M. Llanos, Wang, Huili, Nohalez, Alicia, Aizawa, Emi, Martinez-Redondo, Paloma, Ocampo, Alejandro, Reddy, Pradeep, Roca, Jordi, Maga, Elizabeth A., Esteban, Concepcion Rodriguez, Berggren, W. Travis, Nuñez Delicado, Estrella, Lajara, Jeronimo, Guillen, Isabel, Guillen, Pedro, Campistol, Josep M., Martinez, Emilio A., Ross, Pablo Juan, Izpisua Belmonte, Juan Carlos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.01.2017
• Subjects: Animals; Blastocyst; Cattle; Chimerism; CRISPR-Cas Systems; CRISPR-Cas9; Embryo, Mammalian - cytology; Female; Gene Editing; human naïve pluripotent stem cells; human-cattle chimeric embryo; human-pig chimeric embryo; Humans; interspecies blastocyst complementation; interspecies chimera; Male; Mammals - classification; Mammals - embryology; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; organ and tissue generation; Pluripotent Stem Cells; Rats; Rats, Sprague-Dawley; Sus scrofa; zygote genome editing; organ and tissue generation; human naïve pluripotent stem cells; pluripotent stem cells; interspecies chimera; zygote genome editing; human-pig chimeric embryo; CRISPR-Cas9; interspecies blastocyst complementation; human-cattle chimeric embryo
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.12.036

Interspecies blastocyst complementation enables organ-specific enrichment of xenogenic pluripotent stem cell (PSC) derivatives. Here, we establish a versatile blastocyst complementation platform based on CRISPR-Cas9-mediated zygote genome editing and show enrichment of rat PSC-derivatives in several tissues of gene-edited organogenesis-disabled mice. Besides gaining insights into species evolution, embryogenesis, and human disease, interspecies blastocyst complementation might allow human organ generation in animals whose organ size, anatomy, and physiology are closer to humans. To date, however, whether human PSCs (hPSCs) can contribute to chimera formation in non-rodent species remains unknown. We systematically evaluate the chimeric competency of several types of hPSCs using a more diversified clade of mammals, the ungulates. We find that naïve hPSCs robustly engraft in both pig and cattle pre-implantation blastocysts but show limited contribution to post-implantation pig embryos. Instead, an intermediate hPSC type exhibits higher degree of chimerism and is able to generate differentiated progenies in post-implantation pig embryos. [Display omitted] •Naive rat PSCs robustly contribute to live rat-mouse chimeras•A versatile CRISPR-Cas9 mediated interspecies blastocyst complementation system•Naive rodent PSCs show no chimeric contribution to post-implantation pig embryos•Chimerism is observed with some human iPSCs in post-implantation pig embryos Human pluripotent stem cells robustly engraft into both cattle and pig pre-implantation blastocysts, but show limited chimeric contribution to post-implantation pig embryos.