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In Full Force. Mechanotransduction and Morphogenesis During Homeostasis and Tissue Regeneration

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In Full Force. Mechanotransduction and Morphogenesis During Homeostasis and Tissue Regeneration Journal of Cardiovascular Development and Disease Review In Full Force. Mechanotransduction and Morphogenesis during Homeostasis and Tissue Regeneration Vasiliki Tsata * and Dimitris Beis * Developmental Biology, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece * Correspondence: [email protected] (V.T.); [email protected] (D.B.); Tel.: +3021-0659-7439 (V.T. & D.B.) Received: 7 July 2020; Accepted: 25 September 2020; Published: 1 October 2020 Abstract: The interactions of form and function have been the focus of numerous studies in the context of development and more recently regeneration. Our understanding on how cells, tissues and organs sense and interpret external cues, such as mechanical forces, is becoming deeper as novel techniques in imaging are applied and the relevant signaling pathways emerge. These cellular responses can be found from bacteria to all multicellular organisms such as plants and animals. In this review, we focus on hemodynamic flow and endothelial shear stress during cardiovascular development and regeneration, where the interactions of morphogenesis and proper function are more prominent. In addition, we address the recent literature on the role of extracellular matrix and fibrotic response during tissue repair and regeneration. Finally, we refer to examples where the integration of multi-disciplinary approaches to understand the biomechanics of cellular responses could be utilized in novel medical applications. Keywords: mechanotransduction; development; regeneration; tissue-engineering; biomechanics; cardiac valves 1. Mechanical Stimuli to Guide Biological Processes During the late 1800s, scientists primarily working on bone and/or orthopedics put forward the notion that an extracellular stimulus, such as mechanical load, can instruct a specific tissue response, such as trabecular bone adaptation and remodeling [1–3]. We currently know that the series of events in which a physical force is converted into a cellular response, able to induce in turn a biological process, are regulated and described by the conserved principles of cellular mechanics and mechanotransduction. From bacteria that sense osmotic pressure changes through their membranes and adjust their cytoplasm [4], to plant stems that adapt their growth patterns in response to wind and rain, touching of passing animals [5] or gravity [6], to fracture healing after bone injury [7], all living organisms use stimuli originating from their environment to constantly adjust their behavior, respond to their surroundings and ensure survival. With forces applied to a given cell from seconds to hours, ranging from pico- to nano- newtons and external stimuli spanning changes in i) the stiffness of extracellular matrix (ECM), ii) air and osmotic pressure, iii) compression, contraction, and stretch, iv) shear stress and v) fluid flow, cells respond to stimuli by adapting their cell function and, therefore, key cellular processes such as gene transcription, protein synthesis, proliferation, migration, differentiation and/or apoptosis. This renders mechanotransduction crucial to development, homeostasis, disease progression and regeneration (Figure1). J. Cardiovasc. Dev. Dis. 2020, 7, 40; doi:10.3390/jcdd7040040 www.mdpi.com/journal/jcdd J. Cardiovasc. Dev. Dis. 2020, 7, 40 2 of 18 J. Cardiovasc. Dev. Dis. 2020, 7, x 2 of 19 FigureFigure 1. 1.Examples Examples ofof keykey mechanotransductionmechanotransduction stimuli and occurring cellular cellular events events from from bacteria bacteria toto humans. humans. InIn thisthis review,review, wewe provideprovide anan overviewoverview ofof thethe basicbasic principles that that allow allow cells cells to to sense sense and and integrateintegrate mechanical mechanical cues cues and and discuss discuss how how mechanotransduction mechanotransduction shapes shapes morphogenetic morphogenetic events events during animalduring and animal tissue and development tissue development with a specific with focusa specific on cardiogenesis. focus on cardiogenesis. Furthermore, Furthermore, we summarize we howsummarize different how types different of biomechanical types of biomechanical signaling orchestrate signaling tissueorchestrate remodeling tissue duringremodeling homeostasis during andhomeostasis regeneration. and regeneration. 2.2. Sensing Sensing andand IntegratingIntegrating MechanicalMechanical ForcesForces MechanotransductionMechanotransduction isis aa complex,complex, multi-stepmulti-step reactionreaction cascade.cascade. The The first first steps steps involve involve mechanotransmissionmechanotransmission andand mechanosensing: the the transmission transmission of of an an external, external, mechanical mechanical cue cue to toa amechanosensitive mechanosensitive cell cell component component and and its its subsequent subsequent local, local, active active perception perception by by the the sensor sensor cell. cell. DuringDuring thethe nextnext step,step, describeddescribed asas mechanocoupling,mechanocoupling, stimuli surpassing surpassing a a certain certain threshold threshold are are transducedtransduced intointo anan intracellularintracellular change;change; thisthis mightmight be a biochemicalbiochemical signal signal and/or and/or electrochemical electrochemical activityactivity and and is, is, therefore, therefore, referred referred to asto biochemical as biochemi coupling.cal coupling. The activationThe activation of such of a such signaling a signaling cascade inducescascade the induces mechanoresponse the mechanoresponse of the sensor of cell,the whichsensor is cell, eventually which transferredis eventually to antransferred effector cell to andan initiateseffector itscell response. and initiates its response. SoSo how how does does a mechanicala mechanical stimulus stimulus transform transform into into a subcellular, a subcellular, molecular molecular signal signal with with such such high effihighciency? efficiency? Cells sense, Cells controlsense, andcontrol interpret and interp externalret cues,external whether cues, they whether come fromthey thecome environment from the orenvironment a neighboring or cell,a neighboring by integrating cell, changes by integratin in surfaceg changes parameters in surface through parameters their membranes. through Duetheir to itsmembranes. lipid bilayer Due composition, to its lipid besidesbilayer composition, its role as a physical besides barrierits role thatas a selectivelyphysical barrier allows that the selectively movement ofallows ions andthe moleculesmovement in of and ions out and of cells,molecules the cell in membraneand out of provides cells, the an cell excellent membrane dock provides for a variety an ofexcellent mechanosensitive dock for a molecules. variety of A mechanosensitive plethora of different molecules. biological A structures,plethora of such different as ion orbiological cell–cell junctionalstructures, channels such as andion transmembraneor cell–cell junctional receptors, channels have beenand suggestedtransmembrane as mechanosensors receptors, have and been can besuggested found in as many mechanosensors different cell and types. can Thebe found integration in many of external different cues cell originatingtypes. The fromintegration the ECM of occursexternal through cues highlyoriginating specific from cell–matrix the ECM interactions. occurs through These highly take place specific in specialized cell–matrix sites, interactions. where cell membranesThese take harborplace in the specialized ECM in structures sites, where of specificcell membranes molecular harbor composition the ECM [8 ],in named structures focal of adhesions specific ormolecular focal contacts composition [9]. In turn, [8], thesenamed form focal multi-protein adhesions complexesor focal contacts [10] that [9]. connect In turn, the extracellularthese form spacemulti-protein to the cell’s complexes interior and [10] the that cytoskeleton, connect the through extracellular transmembrane space to receptorsthe cell’s such interior as those and of the the integrincytoskeleton, family through [11,12]. Thetransmembrane extracellular receptors part of the such integrin as those receptor of the anchors integrin defined family ECM [11,12]. proteins, The extracellular part of the integrin receptor anchors defined ECM proteins, like various proteoglycans like various proteoglycans [13,14], while the cytoplasmic tail interacts with proteins of the cytoskeletal [13,14], while the cytoplasmic tail interacts with proteins of the cytoskeletal network, such as actin, J. Cardiovasc. Dev. Dis. 2020, 7, 40 3 of 18 J. Cardiovasc. Dev. Dis. 2020, 7, x 3 of 19 network, such as actin, myosin, tubulin, and paxillin [15]. The latter can further act as a scaffold and recruitmyosin, other tubulin, structural and paxillin and signaling [15]. The elementslatter can likefurther vinculin act as [a16 scaffold,17] and and/or recruit Focal Adhesion other structural Kinase (FAK)and signaling [18,19], one elements of many like protein vinculin tyrosine [16,17] kinases and/or (PTKs), Focal respectively. Adhesion Kinase This creates (FAK) a [18,19] highly, dynamicone of many protein tyrosine kinases (PTKs), respectively. This creates a highly dynamic and tightly and tightly regulated complex that effectively creates a physical continuity between the extracellular regulated complex that effectively creates a physical continuity between the extracellular space and space and the intracellular environment. the intracellular
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