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Abstract: FR-PO757

Identification of TAZ as a Regulator of TGF-β Mediated Fibrosis in iPSC-Derived Organoids

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Yang, Xiaoping, Johns Hopkins University , Baltimore, Maryland, United States
  • Daneshpajouhnejad, Parnaz, Johns Hopkins University SOM, Baltimore, Maryland, United States
  • Delsante, Marco, University of Parma, Parma, Italy
  • Wang, Xiaoxin, Georgetown University, Washington, District of Columbia, United States
  • Takahashi, Shogo, Georgetown University, Washington, District of Columbia, United States
  • Perzel mandell, Kira, Johns Hopkins University , Baltimore, Maryland, United States
  • Halushka, Marc, Johns Hopkins University SOM, Baltimore, Maryland, United States
  • Kopp, Jeffrey B., NIDDK, NIH, Bethesda, Maryland, United States
  • Levi, Moshe, Georgetown University, Washington, District of Columbia, United States
  • Rosenberg, Avi Z., Johns Hopkins University , Baltimore, Maryland, United States
Background

Chronic kidney disease (CKD) progresses by replacement of functional tissue compartments with fibrosis, a maladaptive repair process. Shifting kidney repair away from fibrosis is key to blocking CKD progression. Much research into the mechanisms of fibrosis is performed in rodent models, outside of the human genetic context and time consuming and expensive. By contrast, reductionist two-dimensional cell culture systems consist of single cell types and lack physiological context. Recently, human induced pluripotent stem cell (iPSC)-derived organoids have shown promise in avoiding some of these limitations. We used iPSC-derived organoids to study fibrogenesis and identify anti-fibrotic mechanisms of bile acid receptor agonists acting downstream of TGF-β1.

Methods

Renal organoids were derived from human iPSCs using a modified feeder-free Takasato protocol. Organoids showed glomeruloid (nephrin/podocalyxin-positive), tubular (E-cadherin/lotus lectin-positive), and vascular compartments. TGF-β1 treatments at 0, 5, 10, and 20 ng/mL were tested. FXR, TGFR5 and TAZ targets and extracellular matrix elements were assessed by qPCR, imunoblotting and confocal microscopy.

Results

TGF-β1 treatment of mature organoids induced extracellular matrix elaboration within 48-72 h in a dose-dependent manner with complete disruption of the organoids at the highest. Previously, we have shown that INT767, a dual TGR5/FXR bile acid receptor agonist, blocks TGF-β1-induced fibrogenesis. To understand the intersect between bile acid receptor agonism and TGF-β1-mediated fibrosis, we focused on transcription factors predicted to interact with the collagen 1 locus. TGF-β1 treatment increased tafazzin (TAZ) and TEA domain transcription factor 1 (TEAD1) expression in the organoids with TAZ and TEAD1 nuclear co-localization in tubules. INT767 decreased TAZ and TEAD1 expression and attenuated TGF-β1-induced fibrosis with preservation of mature nephron architecture.

Conclusion

Treatment of iPSC-derived renal organoids with TGF-β1 recapitulated important aspects of kidney fibrosis over a short period compared to traditional model systems. We demonstrated a mechanism downstream of TGF-β1, involving TAZ and TEAD1 transcription factors, with translational therapeutic potential.

Funding

  • NIDDK Support