The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Box 511, CCW 5206c, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Ottawa Institute of Systems Biology, Ottawa, ON K1H 8L1, Canada.
The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Box 511, CCW 5206c, Ottawa, ON K1H 8L6, Canada; Ottawa Institute of Systems Biology, Ottawa, ON K1H 8L1, Canada.
Cell Rep. 2022 Jul 5;40(1):111048. doi: 10.1016/j.celrep.2022.111048.
Tuberous sclerosis complex (TSC) is a multisystem tumor-forming disorder caused by loss of TSC1 or TSC2. Renal manifestations predominately include cysts and angiomyolipomas. Despite a well-described monogenic etiology, the cellular pathogenesis remains elusive. We report a genetically engineered human renal organoid model that recapitulates pleiotropic features of TSC kidney disease in vitro and upon orthotopic xenotransplantation. Time course single-cell RNA sequencing demonstrates that loss of TSC1 or TSC2 affects multiple developmental processes in the renal epithelial, stromal, and glial compartments. First, TSC1 or TSC2 ablation induces transitional upregulation of stromal-associated genes. Second, epithelial cells in the TSC1 and TSC2 organoids exhibit a rapamycin-insensitive epithelial-to-mesenchymal transition. Third, a melanocytic population forms exclusively in TSC1 and TSC2 organoids, branching from MITF Schwann cell precursors. Together, these results illustrate the pleiotropic developmental consequences of biallelic inactivation of TSC1 or TSC2 and offer insight into TSC kidney lesion pathogenesis.
结节性硬化症复合征（TSC）是一种多系统肿瘤形成障碍，由 TSC1 或 TSC2 的缺失引起。肾脏表现主要包括囊肿和血管平滑肌脂肪瘤。尽管有明确的单基因病因，但细胞发病机制仍不清楚。我们报告了一种基因工程人类肾类器官模型，该模型在体外和原位异种移植中再现了 TSC 肾脏疾病的多种表型特征。时间过程单细胞 RNA 测序表明，TSC1 或 TSC2 的缺失会影响肾脏上皮、基质和神经胶质细胞中多个发育过程。首先，TSC1 或 TSC2 的缺失诱导了基质相关基因的过渡上调。其次，TSC1 和 TSC2 类器官中的上皮细胞表现出雷帕霉素不敏感的上皮-间充质转化。第三，黑色素细胞群体仅在 TSC1 和 TSC2 类器官中形成，从 MITF Schwann 细胞前体分支。总之，这些结果说明了 TSC1 或 TSC2 的双等位基因失活的多效性发育后果，并为 TSC 肾脏病变发病机制提供了见解。
