Generation of a Humanized Mesonephros in Pigs via Embryo Complementation
WANG Jiaowei, LI Nan, DAI Zhen, LAI Liangxue*
Organ transplantation is the best way for treating end-stage kidney diseases, but is limited by the shortage of donor organs. Generating human organs in large mammals through embryo complementation holds great potential to solve it. However, it remains unknown whether it is feasible to grow human kidneys in large mammals through this approach. In this study, hiPSCs were transferred with proliferation-promoting gene MYCN and the anti-apoptotic gene BCL2 to enhance the competitiveness and survival ability of cells in pig embryos, and then were induced into naïve state with a special medium (4CL), created an ideal donor cell type for chimeric integration. Besides, the embryo complementation technique was comprehensively optimized and a novel pig model with partial mesonephric-deficient and complete metanephros deficiency was generated. Based on above efforts, human mesonephros kidneys were grown inside nephric-deficient pigs. The proportion of human-derived cells in the chimeric mesonephros reached up to 70%, and the proportion of the mesonephric tubules reach a maximum of 58%. Importantly, these cells expressed functional markers for kidney development, indicating that human donor cells could differentiate into functional cells and hold potential for the formation of metanephros. For the first time, this study validates the feasibility of generating a humanized solid organ in organogenesis-disabled pigs, opening a new avenue to solve the shortage of human organs for transplantation.
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