Kidney organoids derived from human pluripotent stem cells have glomerular- and tubular-like compartments that are largely avascular and immature in static culture. Here we report an in vitro method for culturing kidney organoids under flow on millifluidic chips, which expands their endogenous pool of endothelial progenitor cells and generates vascular networks with perfusable lumens surrounded by mural cells. We found that vascularized kidney organoids cultured under flow had more mature podocyte and tubular compartments with enhanced cellular polarity and adult gene expression compared with that in static controls. Glomerular vascular development progressed through intermediate stages akin to those involved in the embryonic mammalian kidney’s formation of capillary loops abutting foot processes. The association of vessels with these compartments was reduced after disruption of the endogenous VEGF gradient. The ability to induce substantial vascularization and morphological maturation of kidney organoids in vitro under flow opens new avenues for studies of kidney development, disease, and regeneration.
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The data generated in this study are available from the corresponding authors upon request.
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The authors thank P. Galichon for flow cytometry analyses; Y. Yoda and K. Susa for cell culture and immunocytochemistry; S. Jain at The Washington University Kidney Translational Research Center (KTRC; St. Louis, MO, USA) for providing the BJFF hiPSC line; A. Moisan, C. Chen, and S. Uzel for insightful discussions; J. Weaver, B. Roman-Manso, N. Zhou, and M. Ericsson for imaging assistance; and L. Sanders for videography. This study was supported by the US National Institutes of Health (NIH; T32 fellowship training grant DK007527 to N.G.; Subaward U01DK107350 to M.T.V.; R37 grant DK039773 to J.V.B.; UG3 grant TR002155 to J.V.B., M.T.V., J.A.L., and R.M.; grant P30 DK079333 (the BJFF line) supporting The Washington University KTRC), the Harvard Stem Cell Institute (interdisciplinary grant to N.G.; seed grant to R.M. and J.A.L.), Brigham and Women’s Hospital (Research Excellence Award to N.G. and R.M.; Faculty Career Development Award to R.M.), the NIDDK Diabetic Complications Consortium (DiaComp, https://www.diacomp.org; grant DK076169 to R.M.), the NIH (Re)Building a Kidney Consortium (U01DK107350 to K.A.H. and J.A.L.), the Office of Naval Research Vannevar Bush Faculty Fellowship program (award no. N000141612823 to M.S.-S. and J.A.L.), and the Wyss Institute for Biologically Inspired Engineering (D.B.K., K.T.K., D.M., and J.A.L.). J.A.L. thanks the GETTYLAB and S. Lindenfeld for their generous donations in support of this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.