Renal organoid modeling of tuberous sclerosis complex reveals lesion features arise from diverse developmental processes
Adam Pietrobon,
Julien Yockell-Lelièvre,
Trevor A. Flood,
William L. Stanford
Affiliations
Adam Pietrobon
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; Corresponding author
Julien Yockell-Lelièvre
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
Trevor A. Flood
Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada
William L. Stanford
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; Corresponding author
Summary: 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.
