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Abstract: Modeling human kidney function and disease by engineering stem cell fate
Glomerulopathy is a leading cause of end-stage renal disease. An in vitro model of human glomerulus could facilitate therapeutic discovery and illuminate kidney disease mechanisms. Efforts to develop such models are limited by the lack of functional human podocytes, the specialized epithelial cells that encase glomerular capillaries and regulate selective permeability in the glomerulus. Human induced pluripotent stem (iPS) cells have a remarkable capacity to self-renew indefinitely and differentiate into almost any cell type under appropriate conditions, and could potentially serve as an unlimited source of podocytes. Despite recent advances in the derivation of nephron progenitor cells, a method for specific differentiation of human iPS cells into podocytes remains elusive. We developed a highly efficient method for directed differentiation of human iPS cells into mature podocytes that exhibit primary and secondary foot processes. The podocytes also recapitulate the natural tissue-tissue interface and exhibit the selective molecular clearance of the glomerular capillary wall when co-cultured with human glomerular endothelial cells in an organ-on-a-chip microfluidic device. The engineered human glomerulus-on-a-chip also replicates kidney disease phenotypes in vitro. This work could illuminate the mechanisms of human kidney development and disease and provide a functional in vitro system for therapeutic development.
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