Regenerative Medicine, Disease Modeling, and Drug Discovery in Human Pluripotent Stem Cell-derived Kidney Tissue.

Abstract

The multitude of research clarifying critical factors in embryonic organ development has been instrumental in human stem cell research. Mammalian organogenesis serves as the archetype for directed differentiation protocols, subdividing the process into a series of distinct intermediate stages that can be chemically induced and monitored for the expression of stage-specific markers. Significant advances over the past few years include established directed differentiation protocols of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) into human kidney organoids in vitro. Human kidney tissue in vitro simulate the in vivo response when subject to nephrotoxins, providing a novel screening platform during drug discovery to facilitate identification of lead candidates, reduce developmental expenditures, and reduce future rates of drug-induced acute kidney injury. Patient-derived hiPSCs, which bear naturally occurring DNA mutations, may allow for modeling of human genetic diseases to determine pathologic mechanisms and screen for novel therapeutics. In addition, recent advances in genome editing with CRISPR/Cas9 enable to generate specific mutations to study genetic disease with non-mutated lines serving as an ideal isogenic control. The growing population of patients with end-stage kidney disease (ESKD) is a world-wide healthcare problem with higher morbidity and mortality that warrants the discovery of novel forms of renal replacement therapy. Coupling the outlined advances in hiPSC research with innovative bioengineering techniques, such as decellularized kidney and 3D printed scaffolds, may contribute to the development of bioengineered transplantable human kidney tissue as a means of renal replacement therapy.