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HomeNatureSelective inhibition of stromal mechanosensing suppresses cardiac fibrosis

Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis

  • Davis, J. & Molkentin, J. D. Myofibroblasts: trust your heart and let fate decide. J. Mol. Cell. Cardiol. 70, 9–18 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Herrera, J., Henke, C. A. & Bitterman, P. B. Extracellular matrix as a driver of progressive fibrosis. J. Clin. Invest. 128, 45–53 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Herum, K. M., Choppe, J., Kumar, A., Engler, A. J. & McCulloch, A. D. Mechanical regulation of cardiac fibroblast profibrotic phenotypes. Mol. Biol. Cell 28, 1871–1882 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pesce, M. et al. Cardiac fibroblasts and mechanosensation in heart development, health and disease. Nat. Rev. Cardiol. 20, 309–324 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van Putten, S., Shafieyan, Y. & Hinz, B. Mechanical control of cardiac myofibroblasts. J. Mol. Cell. Cardiol. 93, 133–142 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Walker, C. J. et al. Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts. Nat. Biomed. Eng. 5, 1485–1499 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frangogiannis, N. G. Can myocardial fibrosis be reversed? J. Am. Coll. Cardiol. 73, 2283–2285 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Nagaraju, C. K. et al. Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J. Am. Coll. Cardiol. 73, 2267–2282 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Reichardt, I. M., Robeson, K. Z., Regnier, M. & Davis, J. Controlling cardiac fibrosis through fibroblast state space modulation. Cell Signal. 79, 109888 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tschumperlin, D. J. & Lagares, D. Mechano-therapeutics: targeting mechanical signaling in fibrosis and tumor stroma. Pharmacol. Ther. 212, 107575 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frangogiannis, N. G. Cardiac fibrosis. Cardiovasc. Res. 117, 1450–1488 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E. & Blaxall, B. C. Cardiac fibrosis: the fibroblast awakens. Circ. Res. 118, 1021–1040 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sadek, H. & Olson, E. N. Toward the goal of human heart regeneration. Cell Stem Cell 26, 7–16 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kong, P., Christia, P. & Frangogiannis, N. G. The pathogenesis of cardiac fibrosis. Cell. Mol. Life Sci. 71, 549–574 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Emig, R. et al. Passive myocardial mechanical properties: meaning, measurement, models. Biophys. Rev. 13, 587–610 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yamamoto, K. et al. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc. Res. 55, 76–82 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tallquist, M. D. & Molkentin, J. D. Redefining the identity of cardiac fibroblasts. Nat. Rev. Cardiol. 14, 484–491 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ko, T. et al. Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis. Nat. Commun. 13, 3275 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Francisco, J. et al. Blockade of fibroblast YAP attenuates cardiac fibrosis and dysfunction through MRTF-A inhibition. JACC Basic Transl. Sci. 5, 931–945 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mia, M. M. et al. Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function. Cardiovasc. Res. 118, 1785–1804 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Revelo, X. S. et al. Cardiac resident macrophages prevent fibrosis and stimulate angiogenesis. Circ. Res. 129, 1086–1101 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Caliari, S. R. et al. Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression. Integr. Biol. 8, 720–728 (2016).

    Article 

    Google Scholar
     

  • Driesen, R. B. et al. Reversible and irreversible differentiation of cardiac fibroblasts. Cardiovasc. Res. 101, 411–422 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kollmannsberger, P., Bidan, C. M., Dunlop, J. W. C., Fratzl, P. & Vogel, V. Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts. Sci. Adv. 4, eaao4881 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hall, C. et al. Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype. Sci. Rep. 13, 12137 (2023).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Cho, S. et al. Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell-cycle arrest. Dev. Cell 49, 920–935 e925 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Engler, A. J. et al. Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. J. Cell Sci. 121, 3794–3802 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gao, L. et al. Relationship between the efficacy of cardiac cell therapy and the inhibition of differentiation of human iPSC-derived nonmyocyte cardiac cells into myofibroblast-like cells. Circ. Res. 123, 1313–1325 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cho, N., Razipour, S. E. & McCain, M. L. Featured Article: TGF-β1 dominates extracellular matrix rigidity for inducing differentiation of human cardiac fibroblasts to myofibroblasts. Exp. Biol. Med. 243, 601–612 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Speight, P., Kofler, M., Szaszi, K. & Kapus, A. Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFbeta-regulated Smad3. Nat. Commun. 7, 11642 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reichart, D. et al. Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. Science 377, eabo1984 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aldeiri, B. et al. Transgelin-expressing myofibroblasts orchestrate ventral midline closure through TGFβ signalling. Development 144, 3336–3348 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Madl, C. M., Flaig, I. A., Holbrook, C. A., Wang, Y. X. & Blau, H. M. Biophysical matrix cues from the regenerating niche direct muscle stem cell fate in engineered microenvironments. Biomaterials 275, 120973 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Litvinukova, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tucker, N. R. et al. Transcriptional and cellular diversity of the human heart. Circulation 142, 466–482 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Farbehi, N. et al. Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury. eLife 8, e43882 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ren, Z. et al. Single-cell reconstruction of progression trajectory reveals intervention principles in pathological cardiac hypertrophy. Circulation 141, 1704–1719 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Totaro, A., Panciera, T. & Piccolo, S. YAP/TAZ upstream signals and downstream responses. Nat. Cell Biol. 20, 888–899 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kuzmanov, U. et al. Mapping signalling perturbations in myocardial fibrosis via the integrative phosphoproteomic profiling of tissue from diverse sources. Nat. Biomed. Eng. 4, 889–900 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Subramanian, A. et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437–1452 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bugg, D. et al. MBNL1 drives dynamic transitions between fibroblasts and myofibroblasts in cardiac wound healing. Cell Stem Cell 29, 419–433 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stowers, R. S. et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat. Biomed. Eng. 3, 1009–1019 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alexanian, M. et al. Chromatin remodelling drives immune cell-fibroblast communication in heart failure. Nature 635, 434–443 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Amrute, J. M. et al. Targeting immune-fibroblast cell communication in heart failure. Nature 635, 423–433 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, J., Liu, S., Heallen, T. & Martin, J. F. The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat. Rev. Cardiol. 15, 672–684 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Whitehead, A. J., Hocker, J. D., Ren, B. & Engler, A. J. Improved epicardial cardiac fibroblast generation from iPSCs. J. Mol. Cell. Cardiol. 164, 58–68 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, H., Shen, M. & Wu, J. C. Generation of quiescent cardiac fibroblasts derived from human induced pluripotent stem cells. Methods Mol. Biol. 2454, 109–115 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burridge, P. W. et al. Chemically defined generation of human cardiomyocytes. Nat. Methods 11, 855–860 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lian, X. et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc. Natl Acad. Sci. USA 109, E1848–E1857 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Street, K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genom. 19, 477 (2018).

    Article 

    Google Scholar
     

  • La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alquicira-Hernandez, J. & Powell, J. E. Nebulosa recovers single-cell gene expression signals by kernel density estimation. Bioinformatics 37, 2485–2487 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, T. et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Holland, C. H. et al. Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data. Genome Biol. 21, 36 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Skowronek, P. et al. Rapid and in-depth coverage of the (phospho-)proteome with deep libraries and optimal window design for dia-PASEF. Mol. Cell. Proteom. 21, 100279 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Xu, W., Doshi, A., Lei, M., Eck, M. J. & Harrison, S. C. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol. Cell 3, 629–638 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Corsello, S. M. et al. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med. 23, 405–408 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455–461 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Daina, A., Michielin, O. & Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 42717 (2017).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mannhardt, I. et al. Automated contraction analysis of human engineered heart tissue for cardiac drug safety screening. J. Vis. Exp. https://doi.org/10.3791/55461 (2017).

  • Chaturvedi, R. R. et al. Passive stiffness of myocardium from congenital heart disease and implications for diastole. Circulation 121, 979–988 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Rudebusch, J. et al. Dynamic adaptation of myocardial proteome during heart failure development. PLoS ONE 12, e0185915 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

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