TAZ/TEAD complex regulates TGF-β1-mediated fibrosis in iPSC-derived renal organoids
Posted on: 18 May 2021
Preprint posted on 16 April 2021
INT(-767)erupting the profibrotic TAZ effect. Yang and colleagues demonstrate how treatment with a bile acid receptor agonist, INT-767, attenuates TAZ-mediated renal fibrosis progression.
Selected by Sagar Varankar
Categories: cell biology, molecular biology
Background:
Chronic kidney disease (CKD) is a debilitating condition that affects 11-13% of the global population1. Progressive renal fibrosis accompanied by irreversible nephron loss are characteristic of CKD and often refractory to clinical interventions (1,2). To design effective therapies, it is therefore important to understand the diverse biological processes and molecular circuits that contribute to CKD progression.
TGF-β has been extensively studied as an inducer of renal fibrosis and is known to affect diverse molecular processes (3). Despite its obvious role in numerous pathologies, TGF-β signalling is a difficult therapeutic target due to the complex interactome it generates. Hence, recent studies have attempted to identify downstream effectors of TGF-β which can be targeted in the clinic. One such node is the YAP/TAZ signalling axis which is inactive under homeostatic conditions and specifically upregulated by TGF-β in cell line and mouse models of renal fibrosis (3–5). Importantly, TAZ inhibition is reported to attenuate several pro-fibrotic processes (5). However, interspecies differences and the lack of cellular complexity have limited the clinical impact of observations from mouse and cell line models, respectively1.
Recent advances in organoid generation have established tissue-specific model systems from human pluripotent stem cells (hPSCs). These organoids recapitulate several physiological properties inherent to respective tissues, including the cellular heterogeneity and extracellular architecture1. hPSC derived renal organoids were recently developed as platforms for disease modelling and drug screening (6–8). In this preprint, Yang et al., use the modified Takasato protocol (7) to generate an organoid model of renal fibrosis and discern the role of TAZ activity in driving pro-fibrotic signatures.
Key Findings:
TGF-β1 mediated renal fibrosis involves the transcriptional co-activator TAZ:
In the preprint, the authors used hPSCs-derived renal organoids to model fibrosis in response to TGF-β1. TGF-β1 treatment resulted in a dose-dependent up-regulation of extracellular matrix (ECM) secretion and architecture disruption in these organoids. Further, the fibrotic program activated by TGF-β1 was mediated by the transcriptional co-activator TAZ. Interestingly, TAZ expression was also observed in clinical specimens of mild to moderate renal injury. These experiments allowed the authors to model early stages of renal fibrosis and discern associated molecular events.
INT-767 inhibits TGF-β1 induced fibrosis by inhibiting TAZ:
With their fibrosis model, the authors evaluated the effect of small molecules on inhibiting TGF- β1-induced fibrosis. An initial screen identified INT-767 as a potential drug for reversing the pro- fibrotic program. INT-767 is known to bind and activate the bile acid receptors TGR5 and FXR. The authors observed that TGF-β1 treatment inhibited FXR expression in the organoids which was rescued by INT-767. Further, INT-767 inhibited the expression of TAZ and other model of renal fibrosis.
Pro-fibrotic functions of TAZ depend on its differential interaction with TEADs:
With a confirmed role in fibrosis, the authors then investigated the molecular details of TAZ activity. A transcriptional co-activator requires other proteins for its function; hence the authors examined the co-localization of TAZ with a reported interacting partner, TEAD. TGF-β1 attenuated TAZ-TEAD co-localization which was rescued by INT-767. This was confirmed by immunoprecipitation to show TAZ interacted with TEAD in the presence of INT-767. Further, the authors examined the interaction of TAZ with specific TEAD isoforms to assess their role in driving the INT-767 mediated anti-fibrotic effect. TAZ specifically interacted with TEAD1 and TEAD4 (nuclear isoform). The functional role of this crosstalk was examined with a luciferase-reporter assay where TAZ-TEAD4 interaction was specifically responsible for the inhibition of Col1a1 expression.
Why I Chose This Preprint:
My interest in this study stems from the authors’ attempt to understand the molecular mechanisms that drive renal fibrosis. The authors utilize an elegant organoid model to induce and subsequently curb fibrotic programs, thus highlighting the application of this system in drug screening. They present inhibition of fibrosis by INT-767 as a case study and identify the role of TAZ-TEAD interactions in this process. The association of TAZ expression with mild/moderate renal injury recapitulates early stages of disease progression which currently remain poorly understood. Further, with clinically approved bile-acid receptor agonists, the observations obtained from INT-767 treatment could present an interesting avenue for the management of renal fibrosis.
Questions for the authors:
The authors have presented interesting observations in this preprint. Considering the complicated inter-cellular crosstalk identified during fibrosis and functional redundancies of signalling cascades, my questions for the authors are as follows:
- The preprint describes an increase in ECM secretion in response to TGF-β1 treatment. Do you know which cell populations secrete ECM components in this model? Similarly, did you examine expression patterns of FXR to understand whether INT-767 affects fibrosis progression in a cell-autonomous manner?
- As TAZ expression was not observed in cases of severe injury, do you think that TAZ contributes to damage repair at an early stage? Did you observe TAZ upregulation in a subset of cells (epithelial/stromal/endothelial) and does the contribution of TAZ to fibrosis depend on its cell-specific dysregulation?
- From a clinical perspective, did you examine whether FXR expression is dampened in renal fibrotic lesions? Do you think that explant cultures from clinical samples can resolve fibrotic lesions in response to INT-767 treatment and modulate FXR expression?
References:
- Geuens, T., van Blitterswijk, C. A. & LaPointe, V. S. Overcoming kidney organoid challenges for regenerative medicine. npj Regen. Med. 5, (2020).
- Shabaka, A., Cases-Corona, C. & Fernandez-Juarez, G. Therapeutic Insights in Chronic Kidney Disease Progression. Med. 8, 1–12 (2021).
- Gewin, L. The many talents of transforming growth factor-β in the kidney. Opin. Nephrol. Hypertens. 28, 203–210 (2019).
- Patel, S. et al. Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. FASEB J. 33, 9797–9810 (2019).
- Anorga, S. et al. Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype. FASEB J. 32, 2644–2657 (2018).
- Morizane, R. et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Biotechnol. 33, 1193–1200 (2015).
- Takasato, M., Er, P. X., Chiu, H. S. & Little, M. H. Generation of kidney organoids from human pluripotent stem cells. Protoc. 11, 1681–1692 (2016).
- Taguchi, A. et al. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell 14, 53–67 (2014).
doi: https://doi.org/10.1242/prelights.29042
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