대한신장학회

논문분류	춘계학술대회 초록집
제목	Development of new human-derived Induced Pluripotent Stem Cell systems (iPSC) applied to drug discovery for kidney diseases
저자	Maximilian Naujock,Rena Gratz,Nicola Schuster,Jana Droessler,Evrim Erçetin,Karsten Kottig,Martin Schneider,Olivier Radresa,Uwe Andag,Nele Schwarz
출판정보	2022; 2022(1):
키워드
초록	Objectives: Chronic kidney disease (CKD) is characterized by a progressive decline in renal filtration following the loss of functional nephrons. CKD progression eventually leads to end-stage-kidney disease (ESKD) requiring renal replacement therapies. Current drug treatments slow down progression by controlling blood pressure, inflammation and fibrosis but there are still few different drug classes approved for use in patients. Identification and validation of potential new therapeutic mechanisms depend heavily on the availability of relevant disease models. Here we report on the development of a human in vitro iPSC-derived kidney platform. Namely, we developed 2D and 3D iPSC renal models bearing high physiological relevance to native human cell systems and used them for compound screening. Such human derived models are likely to increase the probability of success in drug discovery projects. Methods: We established a range of protocols to differentiate iPSCs into nephron progenitor cells, podocytes, 3D podocyte spheroids, proximal tubular cells and kidney organoids. Differentiated cells were then validated by an in-depth characterization via RT-qPCR, immunostainings, bulk and single-cell RNA sequencing and functional profiling. We used the cryopreservable human iPSC podocytes to perform an unbiased screen in 384w format with a bio-annotated library of 5000 compounds. Results: Morphological, structural and functional analyses confirmed important features of the developed iPSC renal in vitro models. Additionally, the iPSC podocyte screen revealed a number of novel podocyte-protective pathways. Conclusions: Taken together, we generated several iPSC based renal model cells of superior quality that can efficiently support early drug discovery efforts such as compound screening, target identification and target validation. This kidney iPSC platform falls naturally into drug discovery pipelines and enable the integration of patient-derived cellular systems in the progression of drug discovery plans for CKD.
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