Fibrotic extracellular matrix impacts cardiomyocyte phenotype
and function in an iPSC-derived isogenic model of cardiac
fibrosis

J 2024

Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis

NIRO, Francesco, Soraia FERNANDES, Marco CASSANI, Monica APOSTOLICO, Jorge Oliver-De La CRUZ et. al.

Basic information

Original name

Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis

Authors

NIRO, Francesco (380 Italy, belonging to the institution), Soraia FERNANDES, Marco CASSANI, Monica APOSTOLICO, Jorge Oliver-De La CRUZ, Daniel PEREIRA DE SOUSA (620 Portugal, belonging to the institution), Stefania PAGLIARI, Vladimir VINARSKY, Zbyněk ZDRÁHAL (203 Czech Republic, belonging to the institution), David POTĚŠIL (203 Czech Republic, belonging to the institution), Václav PUSTKA (203 Czech Republic, belonging to the institution), Giulio POMPILIO, Elena SOMMARIVA, Davide ROVINA, Angela Serena MAIONE, Luca BERSANINI, Malin BECKER, Marco RASPONI and Giancarlo FORTE (380 Italy)

Edition

Translational Research, NEW YORK, ELSEVIER SCIENCE INC, 2024, 1931-5244

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.800 in 2022

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/j.trsl.2024.07.003

UT WoS

001275554600001

Keywords in English

Decellularized extracellular matrix;Cardiac fibrosis modelling;Induced pluripotent stem cells;iPSC-derived-cardiac fibroblasts;iPSC-derived-cardiomyocytes

Abstract

V originále

Cardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the activation of cardiac fibroblasts (cFbs) to myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictive in vitro models of heart fibrosis has so far hampered the search for innovative treatments, as most of the cellular-based in vitro reductionist models do not take into account the leading role of ECM cues in driving the progression of the pathology. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (α−SMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblasts in vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere assembly, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis.

Links

LM2023042, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii

Investor: Ministry of Education, Youth and Sports of the CR, CIISB - Czech Infrastructure for Integrative Structural Biology

90254, large research infrastructures

Name: e-INFRA CZ II

Citovat

NIRO, Francesco, Soraia FERNANDES, Marco CASSANI, Monica APOSTOLICO, Jorge Oliver-De La CRUZ, Daniel PEREIRA DE SOUSA, Stefania PAGLIARI, Vladimir VINARSKY, Zbyněk ZDRÁHAL, David POTĚŠIL, Václav PUSTKA, Giulio POMPILIO, Elena SOMMARIVA, Davide ROVINA, Angela Serena MAIONE, Luca BERSANINI, Malin BECKER, Marco RASPONI and Giancarlo FORTE. Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis. Translational Research. NEW YORK: ELSEVIER SCIENCE INC, 2024, vol. 273, November 2024, p. 58-77. ISSN 1931-5244. Available from: https://dx.doi.org/10.1016/j.trsl.2024.07.003.

@article{2419626,
   author = {Niro, Francesco and Fernandes, Soraia and Cassani, Marco and Apostolico, Monica and Cruz, Jorge OliverandDe La and Pereira de Sousa, Daniel and Pagliari, Stefania and Vinarsky, Vladimir and Zdráhal, Zbyněk and Potěšil, David and Pustka, Václav and Pompilio, Giulio and Sommariva, Elena and Rovina, Davide and Maione, Angela Serena and Bersanini, Luca and Becker, Malin and Rasponi, Marco and Forte, Giancarlo},
   article_location = {NEW YORK},
   article_number = {November 2024},
   doi = {http://dx.doi.org/10.1016/j.trsl.2024.07.003},
   keywords = {Decellularized extracellular matrix;Cardiac fibrosis modelling;Induced pluripotent stem cells;iPSC-derived-cardiac fibroblasts;iPSC-derived-cardiomyocytes},
   language = {eng},
   issn = {1931-5244},
   journal = {Translational Research},
   title = {Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis},
   url = {https://www.sciencedirect.com/science/article/pii/S1931524424001440},
   volume = {273},
   year = {2024}
}

TY  - JOUR
ID  - 2419626
AU  - Niro, Francesco - Fernandes, Soraia - Cassani, Marco - Apostolico, Monica - Cruz, Jorge Oliver-De La - Pereira de Sousa, Daniel - Pagliari, Stefania - Vinarsky, Vladimir - Zdráhal, Zbyněk - Potěšil, David - Pustka, Václav - Pompilio, Giulio - Sommariva, Elena - Rovina, Davide - Maione, Angela Serena - Bersanini, Luca - Becker, Malin - Rasponi, Marco - Forte, Giancarlo
PY  - 2024
TI  - Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis
JF  - Translational Research
VL  - 273
IS  - November 2024
SP  - 58-77
EP  - 58-77
PB  - ELSEVIER SCIENCE INC
SN  - 19315244
KW  - Decellularized extracellular matrix;Cardiac fibrosis modelling;Induced pluripotent stem cells;iPSC-derived-cardiac fibroblasts;iPSC-derived-cardiomyocytes
UR  - https://www.sciencedirect.com/science/article/pii/S1931524424001440
N2  - Cardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the activation of cardiac fibroblasts (cFbs) to myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictive in vitro models of heart fibrosis has so far hampered the search for innovative treatments, as most of the cellular-based in vitro reductionist models do not take into account the leading role of ECM cues in driving the progression of the pathology. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (α−SMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblasts in vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere assembly, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis.
ER  -

NIRO, Francesco, Soraia FERNANDES, Marco CASSANI, Monica APOSTOLICO, Jorge Oliver-De La CRUZ, Daniel PEREIRA DE SOUSA, Stefania PAGLIARI, Vladimir VINARSKY, Zbyněk ZDRÁHAL, David POTĚŠIL, Václav PUSTKA, Giulio POMPILIO, Elena SOMMARIVA, Davide ROVINA, Angela Serena MAIONE, Luca BERSANINI, Malin BECKER, Marco RASPONI and Giancarlo FORTE. Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis. \textit{Translational Research}. NEW YORK: ELSEVIER SCIENCE INC, 2024, vol.~273, November 2024, p.~58-77. ISSN~1931-5244. Available from: https://dx.doi.org/10.1016/j.trsl.2024.07.003.

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