Extracellular Matrix Proteins and Substrate Stiffness Synergistically Regulate Vascular Smooth Muscle Cell Migration and Cortical Cytoskeleton Organization

Rickel, Alex P.; Sanyour, Hanna J; Leyda, Neil A; Hong, Zhongkui

doi:10.1021/acsabm.0c00100

Cited by 37 publications

(40 citation statements)

References 61 publications

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“…Consistent with these results, substrate ligand presentation of ECM proteins including fibronectin, laminin, and collagen as adhesive ligands in combination with stiffness of the substrate, so called stiffness-by-ligand regulation, induced different cellular responses to stiffness such as differential focal adhesion assembly and cytoskeletal remodeling to substrate stiffness, which are dependent on the ECM ligands (Sazonova et al, 2015 ). To further investigate the influence of stiffness and ECM composition on cell migration, a 2D in vitro model was applied to mimic the blood vessel wall by culturing vascular smooth muscle cells on an elastic polyacrylamide hydrogel with tunable stiffness coated with fibronectin and collagen I (Rickel et al, 2020 ). Measuring the mean squared displacement of these cells exhibited increased migration distance and speed as a consequence of decreased alignment of cortical stress fibers and actin cytoskeleton disorganization in stiffer fibronectin-coated substrates in contrast to cells on collagen I-coated substrates with diminished migration distance in response to stiffness (Rickel et al, 2020 ).…”

Section: Alteration Of Cell Behaviors In Response To Variation Of Celmentioning

confidence: 99%

“…To further investigate the influence of stiffness and ECM composition on cell migration, a 2D in vitro model was applied to mimic the blood vessel wall by culturing vascular smooth muscle cells on an elastic polyacrylamide hydrogel with tunable stiffness coated with fibronectin and collagen I (Rickel et al, 2020 ). Measuring the mean squared displacement of these cells exhibited increased migration distance and speed as a consequence of decreased alignment of cortical stress fibers and actin cytoskeleton disorganization in stiffer fibronectin-coated substrates in contrast to cells on collagen I-coated substrates with diminished migration distance in response to stiffness (Rickel et al, 2020 ). In addition, adult neural stem cells were cultured on an adhesive poly D-lysine-coated surface with laminin, a major ECM proteins in a microenvironment for neural stem cells, stripe-printed on this surface to investigate the role of ECM protein micropatterning on the migration of these cells (Joo et al, 2015 ).…”

Section: Alteration Of Cell Behaviors In Response To Variation Of Celmentioning

confidence: 99%

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Molecular Regulators of Cellular Mechanoadaptation at Cell–Material Interfaces

Nansa

Kim

2020

Front. Bioeng. Biotechnol.

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Diverse essential cellular behaviors are determined by extracellular physical cues that are detected by highly orchestrated subcellular interactions with the extracellular microenvironment. To maintain the reciprocity of cellular responses and mechanical properties of the extracellular matrix, cells utilize a variety of signaling pathways that transduce biophysical stimuli to biochemical reactions. Recent advances in the micromanipulation of individual cells have shown that cellular responses to distinct physical and chemical features of the material are fundamental determinants of cellular mechanosensation and mechanotransduction. In the process of outside-in signal transduction, transmembrane protein integrins facilitate the formation of focal adhesion protein clusters that are connected to the cytoskeletal architecture and anchor the cell to the substrate. The linkers of nucleoskeleton and cytoskeleton molecular complexes, collectively termed LINC, are critical signal transducers that relay biophysical signals between the extranuclear cytoplasmic region and intranuclear nucleoplasmic region. Mechanical signals that involve cytoskeletal remodeling ultimately propagate into the nuclear envelope comprising the nuclear lamina in assistance with various nuclear membrane proteins, where nuclear mechanics play a key role in the subsequent alteration of gene expression and epigenetic modification. These intracellular mechanical signaling cues adjust cellular behaviors directly associated with mechanohomeostasis. Diverse strategies to modulate cell-material interfaces, including alteration of surface rigidity, confinement of cell adhesive region, and changes in surface topology, have been proposed to identify cellular signal transduction at the cellular and subcellular levels. In this review, we will discuss how a diversity of alterations in the physical properties of materials induce distinct cellular responses such as adhesion, migration, proliferation, differentiation, and chromosomal organization. Furthermore, the pathological relevance of misregulated cellular mechanosensation and mechanotransduction in the progression of devastating human diseases, including cardiovascular diseases, cancer, and aging, will be extensively reviewed. Understanding cellular responses to various extracellular forces is expected to provide new insights into how cellular mechanoadaptation is modulated by manipulating the mechanics of extracellular matrix and the application of these materials in clinical aspects.

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Section: Alteration Of Cell Behaviors In Response To Variation Of Celmentioning

confidence: 99%

Section: Alteration Of Cell Behaviors In Response To Variation Of Celmentioning

confidence: 99%

Molecular Regulators of Cellular Mechanoadaptation at Cell–Material Interfaces

Nansa

Kim

2020

Front. Bioeng. Biotechnol.

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“…Hydrogels of low stiffness (2-4 kPa; hereafter called "soft"), intermediate stiffness (10)(11)(12) kPa; hereafter called "medium"), and high stiffness (20-24 kPa; hereafter called "stiff") stiffness approximate the normal and pathological stiffness of mouse arteries [1,2]. This in vitro hydrogel system has been used for molecular and biomechanical analyses of cellular function in response to a given biomechanical stimulus (stiffness) by ECM [1][2][3][4][5][6][7][8][9][10][11][12]. Using this system ( Figure 1A), serum-starved MEFs were cultured on fibronectin-coated hydrogels with 10% fetal bovine serum (FBS) for 9 and 24 hours.…”

Section: Ecm Stiffness Regulates the Levels Of Lamellipodin And Cell mentioning

confidence: 99%

Mechanosensitive Expression of Lamellipodin Governs Cell Cycle Progression and Intracellular Stiffness

Brazzo

Lee

Bae

2020

Preprint

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Cells exhibit pathological behaviors in response to increased extracellular matrix (ECM) stiffness, including accelerated cell proliferation and migration, which are correlated with increased intracellular stiffness and tension. The biomechanical signal transduction of ECM stiffness into relevant molecular signals and resultant cellular processes is mediated through multiple proteins associated with the actin cytoskeleton in lamellipodia. However, the molecular mechanisms by which lamellipodial dynamics regulate cellular responses to ECM stiffening remain unclear. Previous work described that lamellipodin, a phosphoinositide- and actin filament-binding protein that is known mostly for controlling cell migration, promotes ECM stiffness-mediated early cell cycle progression, revealing a potential commonality between the mechanisms controlling stiffness-dependent cell migration and those controlling cell proliferation. However, i) whether and how ECM stiffness affects the levels of lamellipodin expression and ii) whether stiffness-mediated lamellipodin expression is required throughout cell cycle progression and for intracellular stiffness have not been explored. Here, we show that the levels of lamellipodin expression in cells are significantly increased by a stiff ECM and that this stiffness-mediated lamellipodin upregulation persistently stimulates cell cycle progression and intracellular stiffness throughout the cell cycle, from the early G1 phase to M phase. Finally, we show that both Rac activation and intracellular stiffening are required for the mechanosensitive induction of lamellipodin. More specifically, inhibiting Rac1 activation in cells on stiff ECM reduces the levels of lamellipodin expression, and this effect is reversed by the overexpression of activated Rac1 in cells on soft ECM. We thus propose that lamellipodin is a critical molecular lynchpin in the control of mechanosensitive cell cycle progression and intracellular stiffness.

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“…Currently, people attempt to analyze and reveal the hypertension mechanism in single molecule and single cell level (Huang H., et al, 2018;Zhu Y., et al, 2018 and. The cytoskeleton contents, the polymerization and arrangement of actin filaments were directly responsible for the VSMC elasticity (Shen K., et al, 2019;Rickel A.P., et al, 2020). The investigation in single cell level can supplement studies on complicated living organisms or an intact tissue to determine the related pathways that regulate cell elasticity and adhesion (Zhou N., et al, 2017 a and b).…”

Section: Introductionmentioning

confidence: 99%

“…The investigation in single cell level can supplement studies on complicated living organisms or an intact tissue to determine the related pathways that regulate cell elasticity and adhesion (Zhou N., et al, 2017 a and b). Furthermore, cells are in micro-scales and easy to break, and AFM provides a probability to manipulate VSMC at an individual cell level due to its nano-sensitivity under liquid environment (Sanyour H., et al, 2018(Sanyour H., et al, , 2019(Sanyour H., et al, and 2020. The experimental medicines are administered in micro-volume by a pipette and ensured drugs to diffuse and aim the measured cells, and people can fully and perfectly employ AFM to perform a continuous real-time measurement in the absence and presence of drugs on a single cell.…”

Section: Introductionmentioning

confidence: 99%

Atomic force microscopy reveals the role of vascular smooth muscle cell elasticity in hypertension

Zhu

2020

Preprint

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The vascular smooth muscle cell (VSMC) mechanical properties not only provide intrinsic cellular functions, but also influence many vascular and circulation functions in physiology. In this report, the VSMCs of thoracic aorta from 16 week age Wistar-Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHR) were used as research subjects to reveal hypertension mechanism at a single cell level using atomic force microscopy (AFM). The apparent elastic modulus was significantly increased in VSMCs from SHRs compared to those from WKYs. Treatment with cytochalasin D (CD), ML7, Y27632 and lysophosphatidic acid (LPA) modulated VSMC stiffness of WKYs and SHRs. A spectral analysis approach was applied to further investigate the time- dependent change in VSMC elasticity of WKYs and SHRs. This report demonstrated the efficacy of real-time analysis of VSMC elasticity by AFM nano-indentation, and revealed real-time functional differences in biomechanical characteristics of VSMCs with drug treatments.

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Extracellular Matrix Proteins and Substrate Stiffness Synergistically Regulate Vascular Smooth Muscle Cell Migration and Cortical Cytoskeleton Organization

Cited by 37 publications

References 61 publications

Molecular Regulators of Cellular Mechanoadaptation at Cell–Material Interfaces

Molecular Regulators of Cellular Mechanoadaptation at Cell–Material Interfaces

Mechanosensitive Expression of Lamellipodin Governs Cell Cycle Progression and Intracellular Stiffness

Atomic force microscopy reveals the role of vascular smooth muscle cell elasticity in hypertension

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