Challenges in maturation and integration of kidney organoids for stem cell-based renal replacement therapy

Human pluripotent stem cell-derived kidney organoids hold promise for future applications in regenerative medicine. However, significant biological hurdles need to be overcome to enable their use as a transplantable stem cell-derived therapeutic graft. Current kidney organoid protocols do not recapitulate a complete integrated developing kidney, but embryonic kidney transplantations have provided clues for advancing maturation and functionality of kidney organoids. Transplantation, subsequent vascularization, and blood perfusion of kidney organoids improve nephron patterning and maturation, suggesting a role for angiocrine factors as well as metabolic wiring in these processes. Transplanted organoids exhibit filtration, but the resulting filtrate has no apparent exit path for excretion. Improved in vitro patterning of kidney organoids may be required such that a more structurally correct tissue is formed before transplant. Here we review current progress with transplantation of kidney organoids, as well as their engraftment and integration, and identify the key obstacles to therapeutic success and how these might be achieved.