Generation of Tetraploid Organs in Mice [E18.5]

Tetraploidy is rare in mammals but common in plants and fish, a phenomenon that offers evolutionary benefits. In mammals, tetraploid cells naturally occur in the liver, heart, and pancreas. Although previous studies have shown that tetraploid embryonic stem cells (4N-ESCs) can contribute to the liver and heart, the extent of their potential for regenerating entire organs remains underexplored. Here, we injected 4N-ESCs into blastocysts which lacked specific organs due to Hhex, Nkx2.5, and Pdx1 deficiencies, successfully generating functional tetraploid livers, hearts, and pancreata, which are smaller than their diploid counterparts. FACS analyses showed significant contributions of 4N-ESCs, with up to 84.3% of liver cells, 79.5% of heart cells, and 43.6%of pancreatic cells being tdTomato-positive. Our results indicate that 4N-ESCs preferentially contribute to the formation of tetraploid livers and hearts, and contribute to the pancreata. These findings highlight the potential of 4N-ESCs for human organ regeneration and suggest a new strategy for addressing organ shortages in clinical settings.