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.
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This work was supported by the Defense Advanced Research Projects Agency under Cooperative Agreement Number W911NF-12-2-0036 and the Wyss Institute for Biologically Inspired Engineering at Harvard University. S.M. was supported by a Dean’s Postdoctoral Fellowship from Harvard Medical School, a UNCF-Merck Postdoctoral Fellowship, a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund and an NIH/NIDDK Nephrology Training Grant (4T32DK007199-39). We thank the Wyss Institute Microfabrication team for organ-chip production; A. P. Mehr, K. Jang, A. Bahinski and R. Prantil-Baun for helpful discussions; E. Jiang, Y. Torisawa, E.I. Qendro and S. Lightbown for technical assistance, and R. Luna for helpful comments on the manuscript.
D.E.I. and S.M. are authors on a pending patent for methods for the generation of kidney glomerular podocytes from pluripotent stem cells (US patent application 14/950859). D.E.I. is a founder of Emulate, Inc., holds equity in it, and chairs its scientific advisory board.
Supplementary text, tables and video captions. (PDF 1830 kb)
Human iPS-derived podocytes and glomerular endothelial cells cultured in an organ-on-a-chip microfluidic device under fluid flow without strain. (MP4 12230 kb)
Human iPS-derived podocytes and glomerular endothelial cells cultured in an organ-on-a-chip microfluidic device under both fluid flow and mechanical strain. (MP4 10988 kb)
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Musah, S., Mammoto, A., Ferrante, T. et al. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat Biomed Eng 1, 0069 (2017). https://doi.org/10.1038/s41551-017-0069
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