Rat cell-derived kidney generation via interspecies blastocyst complementation in an Osr1-KO mouse model

Interspecies blastocyst complementation (BC) provides a promising approach to generate transplantable organs from pluripotent stem cells (PSCs). However, interspecies kidney generation has remained largely unsuccessful, particularly when using rat PSCs in mouse hosts. Here, we investigated multiple renal-deficient models ( Sall1 -, Ret -, and Osr1 -knockouts [KOs]) through reverse BC (rBC) analyses. We identified Osr1 -KO embryos as lacking both nephron progenitor and ureteric bud lineages, providing a vacant developmental niche for renal reconstruction. Injection of rat embryonic stem cells (ESCs) into Osr1 -KO mouse blastocysts led to robust rat cell contribution and the formation of kidneys predominantly composed of rat in the vacant niche. These findings establish the Osr1 -KO model as a permissive platform for interspecies kidney organogenesis and offer mechanistic insight into developmental compatibility underlying xenogeneic organ generation.