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使用人诱导多能干细胞衍生的肾脏类器官系统建立 - 缺陷肾病模型。

Modeling of -Deficient Kidney Disease Using a Human Induced Pluripotent Stem Cell-Derived Kidney Organoid System.

机构信息

Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.

Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.

出版信息

Cells. 2023 Sep 20;12(18):2319. doi: 10.3390/cells12182319.

DOI:10.3390/cells12182319
PMID:37759541
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10529520/
Abstract

Karyomegalic interstitial nephritis (KIN) is a genetic kidney disease caused by mutations in the FANCD2/FANCI-Associated Nuclease 1 () gene on 15q13.3, which results in karyomegaly and fibrosis of kidney cells through the incomplete repair of DNA damage. The aim of this study was to explore the possibility of using a human induced pluripotent stem cell (hiPSC)-derived kidney organoid system for modeling -deficient kidney disease, also known as KIN. We generated kidney organoids using WTC-11 (wild-type) hiPSCs and -mutant hiPSCs which include KIN patient-derived hiPSCs and -edited hiPSCs (WTC-11 ), created using the CRISPR/Cas9 system in WTC-11-hiPSCs. Kidney organoids from each group were treated with 20 nM of mitomycin C (MMC) for 24 or 48 h, and the expression levels of Ki67 and H2A histone family member X (H2A.X) were analyzed to detect DNA damage and assess the viability of cells within the kidney organoids. Both WTC-11-hiPSCs and -mutant hiPSCs were successfully differentiated into kidney organoids without structural deformities. MMC treatment for 48 h significantly increased the expression of DNA damage markers, while cell viability in both -mutant kidney organoids was decreased. However, these findings were observed in WTC-11-kidney organoids. These results suggest that -mutant kidney organoids can recapitulate the phenotype of -deficient kidney disease.

摘要

巨核细胞性间质性肾炎 (KIN) 是一种遗传性肾脏疾病，由 15q13.3 上的 FANCD2/FANCI 相关核酸内切酶 1 () 基因突变引起，通过不完全修复 DNA 损伤导致肾细胞的巨核化和纤维化。本研究旨在探讨使用人诱导多能干细胞 (hiPSC) 衍生的肾类器官系统来模拟 - 缺陷肾脏疾病（也称为 KIN）的可能性。我们使用 WTC-11（野生型）hiPSCs 和 - 突变 hiPSCs 生成肾类器官，其中包括 KIN 患者来源的 hiPSCs 和使用 CRISPR/Cas9 系统在 WTC-11-hiPSCs 中编辑的 - 突变 hiPSCs (WTC-11)。将每组肾类器官用 20 nM 丝裂霉素 C (MMC) 处理 24 或 48 h，分析 Ki67 和组蛋白家族成员 X (H2A.X) 的表达水平，以检测 DNA 损伤并评估肾类器官内细胞的活力。WTC-11-hiPSCs 和 - 突变 hiPSCs 均成功分化为无结构畸形的肾类器官。MMC 处理 48 h 显著增加了 DNA 损伤标志物的表达，而 - 突变肾类器官中的细胞活力降低。然而，这些发现仅见于 WTC-11- 肾类器官。这些结果表明 - 突变肾类器官可以再现 - 缺陷肾脏疾病的表型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/d8fe78cbe331/cells-12-02319-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/3ced1d7caa0c/cells-12-02319-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/293e0364e841/cells-12-02319-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/ec597731d512/cells-12-02319-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/d8fe78cbe331/cells-12-02319-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/3ced1d7caa0c/cells-12-02319-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/293e0364e841/cells-12-02319-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/ec597731d512/cells-12-02319-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc6d/10529520/d8fe78cbe331/cells-12-02319-g004.jpg

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