Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip

An in vitro model of the human kidney glomerulus—the major site of blood filtration—could facilitate drug discovery and illuminate kidney-disease mechanisms. Microfluidic organ-on-a-chip technology has been used to model the human proximal tubule, yet a kidney-glomerulus-on-a-chip has not been possible because of the lack of functional human podocytes—the cells that regulate selective permeability in the glomerulus. Here, we demonstrate an efficient (over 90%) and chemically defined method for directing the differentiation of human induced pluripotent stem (hiPS) cells into podocytes that express markers for a mature phenotype (nephrin + , WT1 + , podocin + , PAX2 − ) and that exhibit primary and secondary foot processes. We also show that the hiPS-cell-derived podocytes produce glomerular basement-membrane collagen and recapitulate the natural tissue–tissue interface of the glomerulus, as well as the differential clearance of albumin and inulin, when co-cultured with human glomerular endothelial cells in an organ-on-a-chip microfluidic device. The glomerulus-on-a-chip also mimics adriamycin-induced albuminuria and podocyte injury. This in vitro model of human glomerular function with mature human podocytes may facilitate drug development and personalized-medicine applications. An efficient and chemically defined protocol for the differentiation of human induced pluripotent stem cells into podocytes enables the recapitulation of the differential clearance of the human kidney glomerulus in an organ-on-a-chip.