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
Read preprint
(No Ratings Yet)Sign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Restoring mechanophenotype reverts malignant properties of ECM-enriched vocal fold cancer
Teodora Piskova
Germplasm stability in zebrafish requires maternal Tdrd6a and Tdrd6c
Justin Gutkowski
Leukocytes use endothelial membrane tunnels to extravasate the vasculature
Felipe Del Valle Batalla
Also in the molecular biology category:
Germplasm stability in zebrafish requires maternal Tdrd6a and Tdrd6c
Justin Gutkowski
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Green synthesized silver nanoparticles from Moringa: Potential for preventative treatment of SARS-CoV-2 contaminated water
Safieh Shah, Benjamin Dominik Maier
preLists in the cell biology category:
December in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) cell cycle and division 2) cell migration and cytoskeleton 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Matthew Davies et al. |
November in preprints – the CellBio edition
This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression
| List by | Felipe Del Valle Batalla et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
| List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
| List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
| List by | Dey Lab, Amanda Haage |
Also in the molecular biology category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |