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Traction Force Microscopy for Noninvasive Imaging of Cell Forces.
Mulligan JA, Bordeleau F, Reinhart-King CA, Adie SG
(2018) Adv Exp Med Biol 1092: 319-349
MeSH Terms: Biomechanical Phenomena, Extracellular Matrix, Humans, Microscopy, Atomic Force, Models, Biological
Show Abstract · Added April 10, 2019
The forces exerted by cells on their surroundings play an integral role in both physiological processes and disease progression. Traction force microscopy is a noninvasive technique that enables the in vitro imaging and quantification of cell forces. Utilizing expertise from a variety of disciplines, recent developments in traction force microscopy are enhancing the study of cell forces in physiologically relevant model systems, and hold promise for further advancing knowledge in mechanobiology. In this chapter, we discuss the methods, capabilities, and limitations of modern approaches for traction force microscopy, and highlight ongoing efforts and challenges underlying future innovations.
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5 MeSH Terms
Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
Wang W, Lollis EM, Bordeleau F, Reinhart-King CA
(2019) FASEB J 33: 1199-1208
MeSH Terms: Adherens Junctions, Animals, Antigens, CD, Cadherins, Capillary Permeability, Chick Embryo, Endothelium, Vascular, Enzyme Activation, Extracellular Matrix, Female, Focal Adhesion Protein-Tyrosine Kinases, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Transgenic, Phosphorylation, Protein Transport, Tyrosine, src-Family Kinases
Show Abstract · Added April 10, 2019
Tumor vasculature is known to be more permeable than the vasculature found in healthy tissue, which in turn can lead to a more aggressive tumor phenotype and impair drug delivery into tumors. While the stiffening of the stroma surrounding solid tumors has been reported to increase vascular permeability, the mechanism of this process remains unclear. Here, we utilize an in vitro model of tumor stiffening, ex ovo culture, and a mouse model to investigate the molecular mechanism by which matrix stiffening alters endothelial barrier function. Our data indicate that the increased endothelial permeability caused by heightened matrix stiffness can be prevented by pharmaceutical inhibition of focal adhesion kinase (FAK) both in vitro and ex ovo. Matrix stiffness-mediated FAK activation determines Src localization to cell-cell junctions, which then induces increased vascular endothelial cadherin phosphorylation both in vitro and in vivo. Endothelial cells in stiff tumors have more activated Src and higher levels of phosphorylated vascular endothelial cadherin at adherens junctions compared to endothelial cells in more compliant tumors. Altogether, our data indicate that matrix stiffness regulates endothelial barrier integrity through FAK activity, providing one mechanism by which extracellular matrix stiffness regulates endothelial barrier function. Additionally, our work also provides further evidence that FAK is a promising potential target for cancer therapy because FAK plays a critical role in the regulation of endothelial barrier integrity.-Wang, W., Lollis, E. M., Bordeleau, F., Reinhart-King, C. A. Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
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19 MeSH Terms
Endothelial cells on an aged subendothelial matrix display heterogeneous strain profiles in silico.
Kohn JC, Abdalrahman T, Sack KL, Reinhart-King CA, Franz T
(2018) Biomech Model Mechanobiol 17: 1405-1414
MeSH Terms: Animals, Blood Vessels, Computer Simulation, Endothelial Cells, Extracellular Matrix, Male, Mice, Inbred C57BL, Models, Biological, Stress, Mechanical
Show Abstract · Added April 10, 2019
Within the artery intima, endothelial cells respond to mechanical cues and changes in subendothelial matrix stiffness. Recently, we found that the aging subendothelial matrix stiffens heterogeneously and that stiffness heterogeneities are present on the scale of one cell length. However, the impacts of these complex mechanical micro-heterogeneities on endothelial cells have not been fully understood. Here, we simulate the effects of matrices that mimic young and aged vessels on single- and multi-cell endothelial cell models and examine the resulting cell basal strain profiles. Although there are limitations to the model which prohibit the prediction of intracellular strain distributions in alive cells, this model does introduce mechanical complexities to the subendothelial matrix material. More heterogeneous basal strain distributions are present in the single- and multi-cell models on the matrix mimicking an aged artery over those exhibited on the young artery. Overall, our data indicate that increased heterogeneous strain profiles in endothelial cells are displayed in silico when there is an increased presence of microscale arterial mechanical heterogeneities in the matrix.
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The Vasculature in Prediabetes.
Wasserman DH, Wang TJ, Brown NJ
(2018) Circ Res 122: 1135-1150
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Vessels, Cardiovascular Diseases, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Disease Progression, Endothelium, Vascular, Extracellular Matrix, Fatty Acids, Nonesterified, Fibrinolysis, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Inflammation, Insulin Resistance, Life Style, Metabolic Syndrome, Mice, MicroRNAs, Microcirculation, Muscle, Skeletal, Obesity, Prediabetic State, Risk, Weight Loss
Show Abstract · Added March 26, 2019
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.
© 2018 American Heart Association, Inc.
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28 MeSH Terms
Renal fibrosis: Primacy of the proximal tubule.
Gewin LS
(2018) Matrix Biol 68-69: 248-262
MeSH Terms: Animals, Disease Progression, Extracellular Matrix, Fibrosis, Humans, Kidney Tubules, Proximal, Macrophages, Myofibroblasts, Renal Insufficiency, Chronic
Show Abstract · Added March 26, 2019
Tubulointerstitial fibrosis (TIF) is the hallmark of chronic kidney disease and best predictor of renal survival. Many different cell types contribute to TIF progression including tubular epithelial cells, myofibroblasts, endothelia, and inflammatory cells. Previously, most of the attention has centered on myofibroblasts given their central importance in extracellular matrix production. However, emerging data focuses on how the response of the proximal tubule, a specialized epithelial segment vulnerable to injury, plays a central role in TIF progression. Several proximal tubular responses such as de-differentiation, cell cycle changes, autophagy, and metabolic changes may be adaptive initially, but can lead to maladaptive responses that promote TIF both through autocrine and paracrine effects. This review discusses the current paradigm of TIF progression and the increasingly important role of the proximal tubule in promoting TIF both in tubulointerstitial and glomerular injuries. A better understanding and appreciation of the role of the proximal tubule in TIF has important implications for therapeutic strategies to halt chronic kidney disease progression.
Copyright © 2018 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
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The Role of Age-Related Intimal Remodeling and Stiffening in Atherosclerosis.
VanderBurgh JA, Reinhart-King CA
(2018) Adv Pharmacol 81: 365-391
MeSH Terms: Aging, Animals, Atherosclerosis, Extracellular Matrix, Humans, Tunica Intima, Vascular Remodeling, Vascular Stiffness
Show Abstract · Added April 10, 2019
Age-related vascular stiffening is closely associated with cardiovascular risk. The clinical measure of arterial stiffness, pulse wave velocity, reflects bulk structural changes in the media observed with age, but does not reflect intimal remodeling that also drives atherosclerosis. Endothelial barrier integrity is disrupted during early atherogenesis and is regulated by the mechanics and composition of the underlying intima, which undergoes significant atherogenic remodeling in response to age and hemodynamics. Here, we first review the best characterized of these changes, including physiological intimal thickening throughout the arterial tree, fibronectin and collagen deposition, and collagen cross-linking. We then address the most common in vivo and in vitro models used to gain mechanistic insight into the consequences of intimal remodeling. Finally, we consider the impacts of intimal stiffening upon endothelial cell mechanotransduction with emphasis on the emerging impact of increased complexity in cellular traction forces and substrate rigidity upon endothelial barrier integrity.
© 2018 Elsevier Inc. All rights reserved.
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8 MeSH Terms
Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials.
Lampi MC, Reinhart-King CA
(2018) Sci Transl Med 10:
MeSH Terms: Animals, Cell Differentiation, Extracellular Matrix, Fibrosis, Humans, Myofibroblasts, Transforming Growth Factor beta
Show Abstract · Added April 10, 2019
Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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High-Fat, High-Sugar Diet-Induced Subendothelial Matrix Stiffening is Mitigated by Exercise.
Kohn JC, Azar J, Seta F, Reinhart-King CA
(2018) Cardiovasc Eng Technol 9: 84-93
MeSH Terms: Animals, Aorta, Abdominal, Arterial Pressure, Diet, High-Fat, Dietary Sugars, Disease Models, Animal, Elastic Modulus, Exercise Therapy, Extracellular Matrix, Healthy Diet, Male, Mice, Inbred C57BL, Microscopy, Atomic Force, Peripheral Arterial Disease, Pulse Wave Analysis, Risk Reduction Behavior, Time Factors, Vascular Stiffness
Show Abstract · Added December 7, 2017
Consumption of a high-fat, high-sugar diet and sedentary lifestyle are correlated with bulk arterial stiffening. While measurements of bulk arterial stiffening are used to assess cardiovascular health clinically, they cannot account for changes to the tissue occurring on the cellular scale. The compliance of the subendothelial matrix in the intima mediates vascular permeability, an initiating step in atherosclerosis. High-fat, high-sugar diet consumption and a sedentary lifestyle both cause micro-scale subendothelial matrix stiffening, but the impact of these factors in concert remains unknown. In this study, mice on a high-fat, high-sugar diet were treated with aerobic exercise or returned to a normal diet. We measured bulk arterial stiffness through pulse wave velocity and subendothelial matrix stiffness ex vivo through atomic force microscopy. Our data indicate that while diet reversal mitigates high-fat, high-sugar diet-induced macro- and micro-scale stiffening, exercise only significantly decreases micro-scale stiffness and not macro-scale stiffness, during the time-scale studied. These data underscore the need for both healthy diet and exercise to maintain vascular health. These data also indicate that exercise may serve as a key lifestyle modification to partially reverse the deleterious impacts of high-fat, high-sugar diet consumption, even while macro-scale stiffness indicators do not change.
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18 MeSH Terms
Regulation of ATP utilization during metastatic cell migration by collagen architecture.
Zanotelli MR, Goldblatt ZE, Miller JP, Bordeleau F, Li J, VanderBurgh JA, Lampi MC, King MR, Reinhart-King CA
(2018) Mol Biol Cell 29: 1-9
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Collagen, Extracellular Matrix, Female, Glucose, HEK293 Cells, Humans, Intracellular Space, Neoplasm Metastasis, Rats, Serum
Show Abstract · Added April 10, 2019
Cell migration in a three-dimensional matrix requires that cells either remodel the surrounding matrix fibers and/or squeeze between the fibers to move. Matrix degradation, matrix remodeling, and changes in cell shape each require cells to expend energy. While significant research has been performed to understand the cellular and molecular mechanisms guiding metastatic migration, less is known about cellular energy regulation and utilization during three-dimensional cancer cell migration. Here we introduce the use of the genetically encoded fluorescent biomarkers, PercevalHR and pHRed, to quantitatively assess ATP, ADP, and pH levels in MDA-MB-231 metastatic cancer cells as a function of the local collagen microenvironment. We find that the use of the probe is an effective tool for exploring the thermodynamics of cancer cell migration and invasion. Specifically, we find that the ATP:ADP ratio increases in cells in denser matrices, where migration is impaired, and it decreases in cells in aligned collagen matrices, where migration is facilitated. When migration is pharmacologically inhibited, the ATP:ADP ratio decreases. Together, our data indicate that matrix architecture alters cellular energetics and that intracellular ATP:ADP ratio is related to the ability of cancer cells to effectively migrate.
© 2018 Zanotelli, Goldblatt, Miller, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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A novel conduit-based coaptation device for primary nerve repair.
Bamba R, Riley DC, Kelm ND, Cardwell N, Pollins AC, Afshari A, Nguyen L, Dortch RD, Thayer WP
(2018) Int J Neurosci 128: 563-569
MeSH Terms: Animals, Diffusion Tensor Imaging, Disease Models, Animal, Extracellular Matrix, Female, Microsurgery, Nerve Regeneration, Peripheral Nerve Injuries, Rats, Rats, Sprague-Dawley, Sciatic Nerve
Show Abstract · Added October 24, 2018
BACKGROUND - Conduit-based nerve repairs are commonly used for small nerve gaps, whereas primary repair may be performed if there is no tension on nerve endings. We hypothesize that a conduit-based nerve coaptation device will improve nerve repair outcomes by avoiding sutures at the nerve repair site and utilizing the advantages of a conduit-based repair.
METHODS - The left sciatic nerves of female Sprague-Dawley rats were transected and repaired using a novel conduit-based device. The conduit-based device group was compared to a control group of rats that underwent a standard end-to-end microsurgical repair of the sciatic nerve. Animals underwent behavioral assessments at weekly intervals post-operatively using the sciatic functional index (SFI) test. Animals were sacrificed at four weeks to obtain motor axon counts from immunohistochemistry. A sub-group of animals were sacrificed immediately post repair to obtain MRI images.
RESULTS - SFI scores were superior in rats which received conduit-based repairs compared to the control group. Motor axon counts distal to the injury in the device group at four weeks were statistically superior to the control group. MRI tractography was used to demonstrate repair of two nerves using the novel conduit device.
CONCLUSIONS - A conduit-based nerve coaptation device avoids sutures at the nerve repair site and leads to improved outcomes in a rat model. Conduit-based nerve repair devices have the potential to standardize nerve repairs while improving outcomes.
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