Matrix-transmitted paratensile signaling enables myofibroblast – fibroblast cross talk in fibrosis expansion

Abstract

While the concept of intercellular mechanical communication has been revealed, the mechanistic insights have been poorly evidenced in the context of myofibroblast–fibroblast interaction during fibrosis expansion. Here we report and systematically investigate the mechanical force-mediated myofibroblast–fibroblast cross talk via the fibrous matrix, which we termed paratensile signaling. Paratensile signaling enables instantaneous and long-range mechanotransduction via collagen fibers (less than 1 s over 70 μm) to activate a single fibroblast, which is intracellularly mediated by DDR2 and integrin signaling pathways in a calcium-dependent manner through the mechanosensitive Piezo1 ion channel. By correlating in vitro fibroblast foci growth models with mathematical modeling, we demonstrate that the single-cell-level spatiotemporal feature of paratensile signaling can be applied to elucidate the tissue-level fibrosis expansion and that blocking paratensile signaling can effectively attenuate the fibroblast to myofibroblast transition at the border of fibrotic and normal tissue. Our comprehensive investigation of paratensile signaling in fibrosis expansion broadens the understanding of cellular dynamics during fibrogenesis and inspires antifibrotic intervention strategies targeting paratensile signaling.

Application of FRET Biosensors in Mechanobiology and Mechanopharmacological Screening

“…Abundant studies demonstrate that cells can sense and respond to the environment's mechanical properties, such as stiffness (Engler et al, 2006), ECM degradability (Trappmann et al, 2017), viscoelasticity (Chaudhuri et al, 2015), remodeling capacity (Baker et al, 2015;Davidson et al, 2019), porosity (Jiang et al, 2019), topography (Cutiongco et al, 2020), and so forth. As a way of intercellular communication, cells can respond to the paratensile signal exerted by neighboring cells (Liu et al, 2020). In addition, the frictional force generated by blood flow (fluid shear stress, FSS) in the endothelium, can modulate cellular functions (Zhou et al, 2014).…”

“…During the past decades, it has been well-acknowledged that, the mechanical microenvironment plays a crucial role in regulating cellular functions, together with biochemical signals ( Wang et al, 2009 ). The dysfunction of mechanical microenvironments such as shear stress ( Zhou et al, 2014 ), ECM properties ( Bonnans et al, 2014 ) (e.g., stiffness, degradability, remodeling capacity, porosity, topography, internal strain, and intracellular mechanotransduction) ( Humphrey et al, 2014 ) could contribute to the pathogenesis of multiple diseases, including but not limited to atherosclerosis ( Chiu and Chien, 2011 ), fibrosis ( Liu et al, 2020 ), and cancer ( Branco da Cunha et al, 2016 ). As such, elucidating how the mechanical microenvironment influences cell behavior in physiological and pathological conditions, and the successful identification of mechanotransduction-modulating small molecules would pave the way for next-generation disease-intervention strategies.…”

“…As such, elucidating how the mechanical microenvironment influences cell behavior in physiological and pathological conditions, and the successful identification of mechanotransduction-modulating small molecules would pave the way for next-generation disease-intervention strategies. However, conventional biochemical assays (e.g., western blot, immunostaining) are limited in spatiotemporal resolutions in elucidating instant (usually happens within several seconds) and dynamic mechanotransduction processes ( Wang and Wang, 2009 ; Wang et al, 2009 ; Liu et al, 2020 ). Imaging techniques together with genetically encoded FRET biosensors can be a powerful approach for dynamically tracking signal transduction in live cells or tissues with high spatiotemporal resolutions, thus enabling the investigation of mechanotransduction during cell-microenvironment and cell-cell interactions.…”

Engineering Biomaterials and Approaches for Mechanical Stretching of Cells in Three Dimensions

“…To mimic the ECM, hydrogels have been widely used in 3D cell culture. From the aspects of mechanical stretching, hydrogels can not only transmit stretch forces to the resident cells, forcing cells to stretch, but also respond to mechanical stretch itself via structural remodeling and biochemical molecule regulation, all of which can have profound effects on cell behaviors ( Vader et al, 2009 ; Gaul et al, 2018 ; Liu et al, 2020 ; Pei et al, 2020 ). It is therefore reasonable to include mechanical, structural and biochemical considerations when engineering hydrogels for mechanical stretching of cells in three dimensions ( Figure 3 ; Li et al, 2017 ; Davidson et al, 2020 ).…”

“…Cells can sense fiber features (e.g., diameter, length, density and direction), actively remodel the fibrous networks via cell contraction, and respond by adjusting their contractility, migration, alignment and growth ( Holmes et al, 2018 ; Brauer et al, 2019 ; Wang W. Y. et al, 2019 ). Moreover, recent studies have identified a particular important role of the fibrous networks in long-distance cell-cell communications and collective behaviors ( Han et al, 2018 ; Sarker et al, 2019 ; Liu et al, 2020 ). While some reconstituted protein-based biopolymers (e.g., type I collagen) can spontaneously self-assemble into fibrous structures under mild conditions, many widely used biopolymers [e.g., gelatin, sodium alginate, hyaluronic acid (HA)] and most synthetic hydrogels often lack fibrous structural features.…”