Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Jansen Jitske, van den Berge Bartholomeus T, van den Broek Martijn, Maas Rutger J, Daviran Deniz, Willemsen Brigith, Roverts Rona, van der Kruit Marit, Kuppe Christoph, Reimer Katharina C, Di Giovanni Gianluca, Mooren Fieke, Nlandu Quincy, Mudde Helmer, Wetzels Roy, den Braanker Dirk, Parr Naomi, Nagai James S, Drenic Vedran, Costa Ivan G, Steenbergen Eric, Nijenhuis Tom, Dijkman Henry, Endlich Nicole, van de Kar Nicole C A J, Schneider Rebekka K, Wetzels Jack F M, Akiva Anat, van der Vlag Johan, Kramann Rafael, Schreuder Michiel F, Smeets Bart
Аннотация
Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.