Controlled ploidy reduction of pluripotent 4n cells generates 2n cells during mouse embryo development

Cells with high ploidy content are common in mammalian extraembryonic and adult tissues. Cell-to-cell fusion generates polyploid cells during mammalian development and tissue regeneration. However, whether increased ploidy can be occasionally tolerated in embryonic lineages still remains largely unknown. Here, we show that pluripotent, fusion-derived tetraploid cells, when injected in a recipient mouse blastocyst, can generate diploid cells upon ploidy reduction. The generated diploid cells form part of the adult tissues in mouse chimeras. Parental chromosomes in pluripotent tetraploid cells are segregated through tripolar mitosis both randomly and nonrandomly and without aneuploidy. Tetraploid-derived diploid cells show a differentiated phenotype. Overall, we discovered an unexpected process of controlled genome reduction in pluripotent tetraploid cells. This mechanism can ultimately generate diploid cells during mouse embryo development and should also be considered for cell fusion-mediated tissue regeneration approaches.This work was supported by the Ministerio de Ciencia, Innovación y Universidades, (BFU2017-86760-P to M.P.C.) (AEI/FEDER, UE) and the AGAUR grant from Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya, (2017 SGR 689 to M.P.C.). Work in M.P.C. lab was supported by funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 686637 (CellViewer). We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme / Generalitat de Catalunya. KU Leuven C1 funds (C14/16/078 to F.L.), FWO national grants (G097618N to F.L.), Instituto de Salud Carlos III (CP10/00445 to F.L.), a “CRG-Severo Ochoa” predoctoral fellowship (to P.C.), and a grant from the Fundação para a Ciência e a Tecnologia (FCT) (SFRH/BD/76068/2011 to J.F.)