University of Southern California
1 out of 7 Americans develop chronic kidney disease (CKD). When kidney function continues to decline, CKD patients may develop end-stage renal disease (ESRD, or kidney failure). 2 out of 1000 adults in the U.S. develop ESRD and these patients must live on dialysis or get a kidney transplant to survive. Each year, more than $49 billion is spent to treat patients with ESRD and ESRD also greatly reduces longevity and quality of life for patients. Compared to dialysis, kidney transplant offers the best chance of survival, but few donor organs are available. Thus, there is an urgent need for innovative solutions that address the shortage of kidneys available for transplantation. Current strategies towards developing a kidney replacement therapy face significant challenges with limited success. Here we propose a radically different approach to generating a transplantable kidney: the synthetic kidney approach. The synthetic kidney is engineered from native progenitor populations to generate a structure similar to the embryonic kidney. The synthetic kidney is then transplanted into the abdomen of the recipient, where it will continue to grow, differentiate, vascularize and functionally mature in situ by following the normal process of kidney organogenesis. The proposed study is based on our solid technological innovations over the course of the past decade.
Step by step, we have established systems to generate large quantities of high-quality nephron progenitor cells (NPCs) and ureteric bud progenitor cells (UPCs), the two most important building blocks for a developing kidney. We have also succeeded in using cultured NPCs and UPCs to assemble an in vitro self-organizing synthetic kidney, which shows extensive branching, nephron induction, patterning, and maturation. We are thus uniquely positioned to carry out this innovative synthetic kidney project with the goal of solving the shortage of kidneys available for transplantation. With an interdisciplinary research team covering expertise of stem cell, kidney development, kidney physiology, animal models and bioengineering, we will 1) generate a scaled-up transplantable synthetic kidney by combining stem cell technologies and bioengineering strategies; 2) evaluate the growth, differentiation, vascularization, and functional maturation of the transplanted synthetic kidney; 3) determine the therapeutic potential of the synthetic kidney in CKD and ESRD animal models. If the synthetic kidney approach can halt CKD progression and provide alternative organ transplants for ESRD patients, there will be a dramatic reduction in CKD-related complications and dialysis, thereby improving the patient care and reducing health care costs.