Life-supporting functional kidney replacement by integration of embryonic metanephros-bladder composite tissue transplants.

Abstract

Novel transplantable organs need to be developed to address the global organ shortage. Transplantation of embryonic kidney tissue, or metanephros, facilitates glomerular and tubular maturation and offers partial organ functional support. However, adult environments do not permit exponential growth in size, limiting the life-supporting functionality and organ replacement effect of this approach. Here, we developed a novel strategy that combines the fusion of embryonic bladders with multiple anastomoses to the host ureter, enabling a significant increase in metanephros transplantation and urinary tract integration. By surgically anastomosing divided bladder segments, we reconstructed the excretory pathways by merging four metanephroi into each bladder and integrating them with the host ureter. Following the transplantation and integration of 20 metanephroi at the para-aortic region, anephric rats survived for over a month and generated approximately 50,000 nephrons in vivo. Ultrastructural and single-cell- transcriptomic analyses revealed that the maturity of the transplanted metanephroi was comparable to that of adult kidneys, although their small size likely contributed to their decreased urine concentration ability. Postoperative support helped normalize physiological homeostasis, including solute clearance, acid-base balance, electrolyte levels, and kidney hormone levels, within vital ranges. Our findings underscore the functional maturation capacity and dose-dependent therapeutic efficacy of embryonic kidney tissue, suggesting its potential as a transplantable organ system.