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Cardiac fibroblasts and mechanosensation in heart development, health and disease

Abstract

The term ‘mechanosensation’ describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This capacity is related not only to the sensitivity of the cells to tissue motion, but also to the decryption of tissue geometric arrangement and mechanical properties. The cardiac stroma, composed of fibroblasts, has been historically considered a mechanically passive component of the heart. However, the latest research suggests that the mechanical functions of these cells are an active and necessary component of the developmental biology programme of the heart that is involved in myocardial growth and homeostasis, and a crucial determinant of cardiac repair and disease. In this Review, we discuss the general concept of cell mechanosensation and force generation as potent regulators in heart development and pathology, and describe the integration of mechanical and biohumoral pathways predisposing the heart to fibrosis and failure. Next, we address the use of 3D culture systems to integrate tissue mechanics to mimic cardiac remodelling. Finally, we highlight the potential of mechanotherapeutic strategies, including pharmacological treatment and device-mediated left ventricular unloading, to reverse remodelling in the failing heart.

Key points

  • The sensing of mechanical tissue properties is a process related to cell differentiation, maturation and pathology in multicellular organs such as the heart.

  • Remodelling of the cardiac extracellular matrix, which occurs as a consequence of a pathological stimulus, induces changes in the mechanical properties of the myocardium.

  • Variations in the mechanical properties of the myocardium are related to the activation of pro-fibrotic cells (so-called myofibroblasts).

  • Mechanical cues can potentiate pro-fibrotic humoral signalling.

  • The identification of molecular pathways involved in mechanosensation of myofibroblasts facilitates the identification of therapeutic targets that can reverse mechanically induced pathological activation.

  • The possibility that interfering with mechanical cues in vivo might result in cardiac regeneration opens new therapeutic avenues in cardioprotection.

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Fig. 1: The mechanical framework of myocardial cell maturation.
Fig. 2: Cellular force transmission and mechanisms of mechanotransduction.
Fig. 3: Effects of ECM remodelling owing to ageing or compensatory mechanisms on local variations in stiffness.
Fig. 4: Mechanical ‘memory’ underlies chronic pathological cellular phenotypes.
Fig. 5: Integration of diagnostic and experimental pipelines for the evaluation of cardiac mechanotherapeutic approaches.

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Acknowledgements

M.P. is supported by institutional grants from the Italian Ministry of Health (Ricerca Corrente, Ricerca 5 per mille). G.N.D. is supported by the Deutsche Forschungsgemeinschaft (SFB 1444). G.F. is supported by the European Regional Development Fund – Project ENOCH (CZ.02.1.01/0.0/0.0/16_019/0000868) and Project MAGNET (CZ.02.1.01/0.0/0.0/15_003/0000492). H.G. is supported by the European Regional Development Fund through the Operational Program for Competitiveness Factors (under the projects HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, POCI-01-0145-FEDER-022122, UIDB/04539/2020 and UIDP/04539/2020). A.R. is supported by the Spanish Ministry of Economy and Competitiveness (RTI2018-095377-B-100), Instituto de Salud Carlos III-ISCIII/FEDER (TerCel RD16/0011/0024), AGAUR (2017-SGR-899) and CERCA Programme Generalitat de Catalunya. P.R.-C. is supported by the Spanish Ministry of Science and Innovation (PID2019-110298GB-I00), the European Commission (H2020-FETPROACT-01-2016-731957), the ICREA Academia prize for excellence in research, Fundació la Marató de TV3 (201936-30-31) and la Caixa Foundation (agreement LCF/PR/HR20/52400004). J.P.G.S. is supported by a European Union H2020 programme grant EVICARE (725229) and BRAV (874827), and the Gravitation Program (Materials Driven Regeneration 024.003.013) by the Netherlands Organization for Scientific Research. C.T. and S.V.L. are supported by the Deutsche Forschungsgemeinschaft (SFB 1470).

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M.P. and S.V.L. contributed to the discussion of manuscript content. All the authors contributed to writing, reviewing and editing the manuscript before submission.

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Correspondence to Maurizio Pesce or Sophie Van Linthout.

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C.T. has received speaker fees and has contributed to congresses organized by Abbott, Abiomed, AstraZeneca, Bayer, Boehringer-Ingelheim, Novartis, Pfizer and Servier. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks Nikolaos Frangogiannis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Costameres

Submembranous, Z-line-associated structures found in striated muscle that have important roles in force transmission from the sarcomeres to the sarcolemma and the extracellular matrix, maintenance of mechanical integrity of the sarcolemma, and orchestration of mechanically related signalling.

Dense plaques

Also known as dense bodies. Intercellular adhesion complexes that are functional equivalents of the Z-discs in the striated muscle and fulfil a mechanical function that allows the coordinated contraction of smooth muscle cells.

Dystroglycan complex

A large multicomponent complex that is composed of transmembrane, cytoplasmic and extracellular proteins, including dystrophin, sarcoglycans, dystroglycan, dystrobrevins, syntrophins, sarcospan, caveolin 3 and nitric oxide synthase, and has both mechanical stabilizing and signalling roles in mediating interactions between the cytoskeleton, plasma membrane and extracellular matrix.

Euchromatin

A less condensed chromatin than heterochromatin and more accessible to transcription factors.

Heterochromatin

A densely packed chromatin that is inaccessible to transcription factors and has an important role in maintaining the structural and functional integrity of specific chromosomal regions, such as centromeres and telomeres.

Podosomes

Actin-based dynamic protrusions of the plasma membrane that act as sites of attachment to, and degradation of, the extracellular matrix.

Rigidity

The capacity of a material to withstand deformation when subjected to mechanical loading (such as tension).

Strain

Strain (ε) is the deformation of a material or tissue when subjected to stress; stress (σ) is an internal loading on a material caused by an external force.

Stiffness

The extent to which a material resists deformation in response to an applied load, and is the inverse of compliance.

Teleost

Teleost fish are the most species-rich vertebrate clade, roughly making up half of the existing vertebrate species on the planet, and have extensive genetic and phenotypic variation, resulting in their use in biodiversity and genome evolution studies.

Young’s modulus

(E). Also referred to as modulus of elasticity, it is a property of the material that indicates how easily it can stretch and deform, and is defined as the ratio of tensile stress (σ) to tensile strain (ε).

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Pesce, M., Duda, G.N., Forte, G. et al. Cardiac fibroblasts and mechanosensation in heart development, health and disease. Nat Rev Cardiol (2022). https://doi.org/10.1038/s41569-022-00799-2

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