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Light-driven biological actuators to probe the rheology of 3D microtissues.

ABSTRACT: The mechanical properties of biological tissues are key to their physical integrity and function. Although external loading or biochemical treatments allow the estimation of these properties globally, it remains difficult to assess how such external stimuli compare with cell-generated contractions. Here we engineer microtissues composed of optogenetically-modified fibroblasts encapsulated within collagen. Using light to control the activity of RhoA, a major regulator of cellular contractility, we induce local contractions within microtissues, while monitoring microtissue stress and strain. We investigate the regulation of these local contractions and their spatio-temporal distribution. We demonstrate the potential of our technique for quantifying tissue elasticity and strain propagation, before examining the possibility of using light to create and map local anisotropies in mechanically heterogeneous microtissues. Altogether, our results open an avenue to guide the formation of tissues while non-destructively charting their rheology in real time, using their own constituting cells as internal actuators.

SUBMITTER: Mery A

PROVIDER: S-EPMC9911700 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Light-driven biological actuators to probe the rheology of 3D microtissues.

Méry Adrien A Ruppel Artur A Revilloud Jean J Balland Martial M Cappello Giovanni G Boudou Thomas T

Nature communications 20230209 1

The mechanical properties of biological tissues are key to their physical integrity and function. Although external loading or biochemical treatments allow the estimation of these properties globally, it remains difficult to assess how such external stimuli compare with cell-generated contractions. Here we engineer microtissues composed of optogenetically-modified fibroblasts encapsulated within collagen. Using light to control the activity of RhoA, a major regulator of cellular contractility, w ...[more]

PMID: 36759504

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Project description:Engineered heart tissues (EHTs) present a potential solution to some of the current challenges in the treatment of heart disease; however, the development of mature, adult-like cardiac tissues remains elusive. Mechanical stimuli have been observed to improve whole-tissue function and cardiomyocyte (CM) maturation, although our ability to fully utilize these mechanisms is hampered, in part, by our incomplete understanding of the mechanobiology of EHTs. In this work, we leverage experimental data, produced by a mechanically tunable experimental setup, to introduce a tissue-specific computational modeling pipeline of EHTs. Our new modeling pipeline generates simulated, image-based EHTs, capturing ECM and myofibrillar structure as well as functional parameters estimated directly from experimental data. This approach enables the unique estimation of EHT function by data-based estimation of CM active stresses. We use this experimental and modeling pipeline to study different mechanical environments, where we contrast the force output of the tissue with the computed active stress of CMs. We show that the significant differences in measured experimental forces can largely be explained by the levels of myofibril formation achieved by the CMs in the distinct mechanical environments, with active stress showing more muted variations across conditions. The presented model also enables us to dissect the relative contributions of myofibrils and extracellular matrix to tissue force output, a task difficult to address experimentally. These results highlight the importance of tissue-specific modeling to augment EHT experiments, providing deeper insights into the mechanobiology driving EHT function. STATEMENT OF SIGNIFICANCE: Engineered heart tissues (EHTs) have the potential to revolutionize the way heart disease is treated. However, developing mature cardiomyocytes (CM) in these tissues remains a challenge due, in part, to our incomplete understanding of the fundamental biomechanical mechanisms that drive EHT development. This work integrates the experimental data of an EHT platform developed to study the influence of mechanics in CM maturation with computational biomechanical models. This approach is used to augment conclusions obtained in-vitro - by measuring quantities such as cell stress and strain - and to dissect the relevance of each component in the whole tissue performance. Our results show how a combination of specialized in-silico and in-vitro approaches can help us better understand the mechanobiology of EHTs.

Dataset Information

Light-driven biological actuators to probe the rheology of 3D microtissues.

Publications

Light-driven biological actuators to probe the rheology of 3D microtissues.

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