期刊
DEVELOPMENT
卷 149, 期 9, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.200198
关键词
Nephrotic syndrome; Human iPSC-derived kidney organoids; 2D iPSC-derived podocytes
资金
- Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- NWO Veni grant) [091 501 61 81 01 36]
- Dutch Kidney Foundation (Nierstichting) [19OK005]
- Netherlands Organization for Scientific Research (NWO Off road grant) [451001034]
- European Research Council Advanced Investigator grant [H2020-ERC-2017-ADV-788982-COLMIN]
- NWO [VI.Veni.192.094]
- Netherlands Organization for Scientific Research (NWO VIDI grant) [016.156.363, 016.156.454]
- German Ministry of Education and Science (Bundesministerium fur Bildung und Forschung)
- Radboud University: Radboud Universiteit
- Dutch Kidney Foundation [19OK005, 15OKG16, 14A3D104, 18OKG05, 18OI14]
Using organoid podocytes as a model, this study investigated idiopathic nephrotic syndrome and found that repaired organoids exhibited improved functionality, providing a valuable tool for disease modeling and therapy development.
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.
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