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Disrupting biological sensors of force promotes tissue regeneration in large organisms.

ABSTRACT: Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

SUBMITTER: Chen K

PROVIDER: S-EPMC8421385 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Disrupting biological sensors of force promotes tissue regeneration in large organisms.

Chen Kellen K Kwon Sun Hyung SH Henn Dominic D Kuehlmann Britta A BA Tevlin Ruth R Bonham Clark A CA Griffin Michelle M Trotsyuk Artem A AA Borrelli Mimi R MR Noishiki Chikage C Padmanabhan Jagannath J Barrera Janos A JA Maan Zeshaan N ZN Dohi Teruyuki T Mays Chyna J CJ Greco Autumn H AH Sivaraj Dharshan D Lin John Q JQ Fehlmann Tobias T Mermin-Bunnell Alana M AM Mittal Smiti S Hu Michael S MS Zamaleeva Alsu I AI Keller Andreas A Rajadas Jayakumar J Longaker Michael T MT Januszyk Michael M Gurtner Geoffrey C GC

Nature communications 20210906 1

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mecha ...[more]

PMID: 34489407

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Project description:Mechanical forces play key roles in biological processes such as cell migration and sensory perception. In recent years, molecular force sensors have been developed as tools for in situ force measurements. Here, we use all-atom steered molecular dynamics simulations to predict and study the relationship between design parameters and mechanical properties for three types of molecular force sensors commonly used in cellular biological research: two peptide and one DNA based. The peptide-based sensors consist of a pair of fluorescent proteins that can undergo Förster resonance energy transfer, linked by spider silk (GPGGA)n or synthetic (GGSGGS)n disordered regions. The DNA-based sensor consists of two fluorophore-labeled strands of DNA that can be unzipped or sheared upon force application with a Förster resonance energy transfer signal as readout of dissociation. We simulated nine sensors, three of each kind. After equilibration, flexible peptide linkers of three different lengths were stretched by applying forces to their N- and C-terminal Cα atoms in opposite directions. Similarly, we equilibrated a DNA-based sensor and pulled on the phosphate atom of the terminal guanine of one strand and a selected phosphate atom on the other strand for pulling in the opposite direction. These simulations were performed at constant velocity (0.01-10 nm/ns) and constant force (10-500 pN) for all versions of the sensors. Our results show how the force response of these sensors depends on their length, sequence, configuration, and loading rate. Mechanistic insights gained from simulations analyses indicate that interpretation of experimental results should consider the influence of transient formation of secondary structure in peptide-based sensors and of overstretching in DNA-based sensors. These predictions can guide optimal fluorophore choice and facilitate the rational design of new sensors for use in protein, DNA, hybrid systems, and molecular devices.

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Disrupting biological sensors of force promotes tissue regeneration in large organisms.

Publications

Disrupting biological sensors of force promotes tissue regeneration in large organisms.

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