Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling

Abstract

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. Here, we report human induced pluripotent stem cell derived kidney organoids containing a podocyte population that heads towards adult podocytes and were superior compared to 2D counterparts, based on scRNA 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 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.Summary StatementKidney organoid podocytes allow personalized nephrotic sydrome modeling,

Understanding the Current Landscape of Kidney Disease in Canada to Advance Precision Medicine Guided Personalized Care

“…We and others have gained new insight into the mechanisms contributing to kidney diseases such as APOL1 nephropathy, PKD, and nephrotic syndrome using iPSC-derived kidney organoids. 93 - 100 CRISPR/Cas9 edited iPSC and the use of patient-derived iPSC are beginning to shed light on the kidney developmental processes and mechanistic pathways that contribute to disease. These particularly powerful approaches will eventually enable us to study patient-specific disease effects that will lead to the personalization of treatment strategies in the future.…”

Human scattered tubular cells represent a heterogeneous population of glycolytic dedifferentiated proximal tubule cells

“…Procedures were performed according to [16]; see Supplementary materials and methods for details. For formalin-fixed, paraffin-embedded (FFPE) tissue, STC markers were previously validated by costaining with CD24 and/or CD133 [4].…”

“…A workflow similar to that described in [16] was used; please see Supplementary materials and methods and supplementary material, Figure S2, for a detailed description.…”

Geben Sie acht auf Ihre Nieren – erst recht nach einer COVID-19-Erkrankung

“…Dabei zeigte bereits eine Autopsiestudie des UKE Hamburg zu Beginn der Pandemie, dass bei den an COVID-19 Verstorbenen das Nierengewebe geschädigt war [ 1 ]. Eine Studie aus Aachen [ 2 ], die Ende 2021 publiziert wurde, wies nach: SARS-CoV-2 infiziert Nierenzellen und dieser Prozess ist mit einer tubulointerstitiellen Nierenfibrose, also einer Vernarbung des Nierengewebes, assoziiert. Was bedeutet das konkret für Menschen, die an COVID-19 erkrankt waren?…”