Cyclic Strain and Interstitial Flow Modulate Cardiac Fibroblast Phenotype Through Angiotensin II and TGF-β Pathways

2011 ◽  
Author(s):  
Peter A. Galie ◽  
Jan P. Stegemann
Keyword(s):  
Interstitial Fluid ◽  
Cardiac Fibroblasts ◽  
Cyclic Strain ◽  
Mechanical Stimuli ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
Matrix Deposition ◽  
Myofibroblast Phenotype ◽  
Fibrotic Scar ◽  
Extracellular Matrix Deposition

A fibrotic scar in the myocardium is characterized by excessive extracellular matrix deposition, loss of functioning cardiomyocytes, and the transition of healthy cardiac fibroblasts to a myofibroblast phenotype. Previous research has suggested that the myofibroblast transition is mediated by mechanical stimuli including cyclic strain [1–2] and interstitial fluid flow [3–5].

scholarly journals Interstitial flow promotes macrophage polarization toward an M2 phenotype

2018 ◽  
Vol 29 (16) ◽  
pp. 1927-1940 ◽  
Author(s):  
Ran Li ◽  
Jean Carlos Serrano ◽  
Hao Xing ◽  
Tara A. Lee ◽  
Hesham Azizgolshani ◽  
...  
Keyword(s):  
Fluid Flow ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cell ◽  
Interstitial Fluid ◽  
Macrophage Polarization ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
M2 Polarization ◽  
Tumor Tissues

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

scholarly journals Hyaluronan in intestinal homeostasis and inflammation: implications for fibrosis

2011 ◽  
Vol 301 (6) ◽  
pp. G945-G949 ◽  
Author(s):  
Carol A. de la Motte
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Intestinal Inflammation ◽  
Cellular Mechanisms ◽  
Matrix Component ◽  
Matrix Deposition ◽  
Fibrotic Tissue ◽  
Myofibroblast Phenotype ◽  
Extracellular Matrix Deposition ◽  
Chronic Intestinal Inflammation

The causes of fibrosis, or the inappropriate wound healing, that follows chronic intestinal inflammation are not well defined and likely involve the contributions of multiple cellular mechanisms. As other articles in this series confirm, inflammatory cytokines clearly play a role in driving cell differentiation to the myofibroblast phenotype, promoting proliferation and extracellular matrix deposition that are characteristic of fibrotic tissue. However, controlling the balance of cytokines produced and process of myofibroblast differentiation appears to be more complex. This review considers ways in which hyaluronan, an extracellular matrix component that is remodeled during the progression of colitis, may provide indirect as well as direct cues that influence the balancing act of intestinal wound healing.

scholarly journals Mechanism underlying increased cardiac extracellular matrix deposition in perinatal nicotine-exposed offspring

2020 ◽  
Vol 319 (3) ◽  
pp. H651-H660
Author(s):  
Tsai-Der Chuang ◽  
Aamir Ansari ◽  
Celia Yu ◽  
Reiko Sakurai ◽  
Amir Harb ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Rat Model ◽  
Cardiac Dysfunction ◽  
Cardiac Fibroblasts ◽  
Underlying Mechanism ◽  
Nicotine Exposure ◽  
Collagen Deposition ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition ◽  
Mechanistic Basis

Using an established rat model and cultured primary neonatal cardiac fibroblasts, we show that nicotine mediated MIAT induction as the underlying mechanism for the excessive cardiac collagen deposition. These observations provide mechanistic basis for the increased predisposition to cardiac dysfunction following perinatal cigarette/nicotine exposure and offer novel potential therapeutic targets.

scholarly journals Autologous Gradient Formation Under Differential Interstitial Fluid Flow Environments

2021 ◽  
Author(s):  
Caleb Stine ◽  
Jennifer Munson
Keyword(s):  
Fluid Flow ◽  
Interstitial Fluid ◽  
Single Cells ◽  
Specific Cell ◽  
Minimal Distance ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
Element Analysis ◽  
Gradient Formation ◽  
The Brain

Fluid flow and chemokine gradients play a large part in not only regulating homeostatic processes in the brain, but also in pathologic conditions by directing cell migration. Tumor cells in particular are superior at invading into the brain resulting in tumor recurrence. One mechanism that governs cellular invasion is autologous chemotaxis, whereby pericellular chemokine gradients form due to interstitial fluid flow (IFF) leading cells to migrate up the gradient. Glioma cells have been shown to specifically use CXCL12 to increase their invasion under heightened interstitial flow. Computational modeling of this gradient offers better insight into the extent of its development around single cells, yet very few conditions have been modelled. In this paper, a computational model is developed to investigate how a CXCL12 gradient may form around a tumor cell and what conditions are necessary to affect its formation. Through finite element analysis using COMSOL and coupled convection-diffusion/mass transport equations, we show that velocity (IFF magnitude) has the largest parametric effect on gradient formation, multidirectional fluid flow causes gradient formation in the direction of the resultant which is governed by IFF magnitude, common treatments and flow patterns have a spatiotemporal effect on pericellular gradients, exogenous background concentrations can abrogate the autologous effect depending on how close the cell is to the source, that there is a minimal distance away from the tumor border required for a single cell to establish an autologous gradient, and finally that the development of a gradient formation is highly dependent on specific cell morphology.

Fibroblast alignment under interstitial fluid flow using a novel 3-D tissue culture model

2003 ◽  
Vol 284 (5) ◽  
pp. H1771-H1777 ◽  
Author(s):  
Chee Ping Ng ◽  
Melody A. Swartz
Keyword(s):  
Tissue Culture ◽  
Interstitial Fluid ◽  
Three Dimensional ◽  
Dermal Fibroblasts ◽  
Matrix Remodeling ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
Tissue Organization ◽  
Culture Model ◽  
Tissue Culture Model

Interstitial flow is an important component of the microcirculation and interstitial environment, yet its effects on cell organization and tissue architecture are poorly understood, in part due to the lack of in vitro models. To examine the effects of interstitial flow on cell morphology and matrix remodeling, we developed a tissue culture model that physically supports soft tissue cultures and allows microscopic visualization of cells within the three-dimensional matrix. In addition, pressure-flow relationships can be continuously monitored to evaluate the bulk hydraulic resistance as an indicator of changes in the overall matrix integrity. We observed that cells such as human dermal fibroblasts aligned perpendicular to the direction of interstitial flow. In contrast, fibroblasts in static three-dimensional controls remained randomly oriented, whereas cells subjected to fluid shear as a two-dimensional monolayer regressed. Also, the dynamic measurements of hydraulic conductivity suggest reorganization toward a steady state. These primary findings help establish the importance of interstitial flow on the biology of tissue organization and interstitial fluid balance.

scholarly journals Autologous Gradient Formation under Differential Interstitial Fluid Flow Environments

Biophysica ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 16-33
Author(s):  
Caleb A. Stine ◽  
Jennifer M. Munson
Keyword(s):  
Fluid Flow ◽  
Interstitial Fluid ◽  
Single Cells ◽  
Specific Cell ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
Element Analysis ◽  
Convection Diffusion ◽  
Gradient Formation ◽  
The Brain

Fluid flow and chemokine gradients play a large part in not only regulating homeostatic processes in the brain, but also in pathologic conditions by directing cell migration. Tumor cells in particular are superior at invading into the brain resulting in tumor recurrence. One mechanism that governs cellular invasion is autologous chemotaxis, whereby pericellular chemokine gradients form due to interstitial fluid flow (IFF) leading cells to migrate up the gradient. Glioma cells have been shown to specifically use CXCL12 to increase their invasion under heightened interstitial flow. Computational modeling of this gradient offers better insight into the extent of its development around single cells, yet very few conditions have been modelled. In this paper, a computational model is developed to investigate how a CXCL12 gradient may form around a tumor cell and what conditions are necessary to affect its formation. Through finite element analysis using COMSOL and coupled convection-diffusion/mass transport equations, we show that velocity (IFF magnitude) has the largest parametric effect on gradient formation, multidirectional fluid flow causes gradient formation in the direction of the resultant which is governed by IFF magnitude, common treatments and flow patterns have a spatiotemporal effect on pericellular gradients, exogenous background concentrations can abrogate the autologous effect depending on how close the cell is to the source, that there is a minimum distance away from the tumor border required for a single cell to establish an autologous gradient, and finally that the development of a gradient formation is highly dependent on specific cell morphology.

Dynamics of Calcium Signal and Leukotriene C4Release in Mast Cells Network Induced by Mechanical Stimuli and Modulated by Interstitial Fluid Flow

2015 ◽  
Vol 8 (1) ◽  
pp. 67-81 ◽  
Author(s):  
Wei Yao ◽  
Hongwei Yang ◽  
Yabei Li ◽  
Guanghong Ding
Keyword(s):  
Fluid Flow ◽  
Mast Cells ◽  
Intracellular Calcium ◽  
Signaling Pathways ◽  
Interstitial Fluid ◽  
Calcium Signal ◽  
Mechanical Stimuli ◽  
Interstitial Fluid Flow ◽  
Crac Channels ◽  
Intracellular Ca

AbstractMast cells (MCs) play an important role in the immune system. Through connective tissues, mechanical stimuli activate intracellular calcium signaling pathways, induce a variety of mediators including leukotriene C4(LTC4) release, and affect MCs’ microenvironment. This paper focuses on MCs’ intracellular calcium dynamics and LTC4release responding to mechanical stimuli, explores signaling pathways in MCs and the effect of interstitial fluid flow on the transport of biological messengers and feedback in the MCs network. We use a mathematical model to show that (i) mechanical stimuli including shear stress induced by interstitial fluid flow can activate mechano-sensitive (MS) ion channels on MCs’ membrane and allow Ca2+entry, which increases intracellular Ca2+concentration and leads to LTC4release; (ii) LTC4in the extracellular space (ECS) acts on surface cysteinyl leukotriene receptors (LTC4R) on adjacent cells, leading to Ca2+influx through Ca2+release-activated Ca2+(CRAC) channels. An elevated intracellular Ca2+concentration further stimulates LTC4release and creates a positive feedback in the MCs network. The findings of this study may facilitate our understanding of the mechanotransduction process in MCs induced by mechanical stimuli, contribute to understanding of interstitial flow-related mechanobiology in MCs network, and provide a methodology for quantitatively analyzing physical treatment methods including acupuncture and massage in traditional Chinese medicine (TCM).

scholarly journals Multilayer microfluidic platform for the study of luminal, transmural, and interstitial flow

2022 ◽  
Author(s):  
Gi-hun Lee ◽  
Stephanie A Huang ◽  
Wen Yih Aw ◽  
Mitesh Rathod ◽  
Crescentia Cho ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Fluid Velocity ◽  
Expression Patterns ◽  
Fluid Pressure ◽  
Solid Cancer ◽  
Mechanical Stimuli ◽  
Interstitial Fluid Flow ◽  
Flowing Fluid ◽  
Microfluidic Platform ◽  
Gene And Protein Expression

Abstract Efficient delivery of oxygen and nutrients to tissues requires an intricate balance of blood, lymphatic, and interstitial fluid pressures, and gradients in fluid pressure drive the flow of blood, lymph, and interstitial fluid through tissues. While specific fluid mechanical stimuli, such as wall shear stress, have been shown to modulate cellular signaling pathways along with gene and protein expression patterns, an understanding of the key signals imparted by flowing fluid and how these signals are integrated across multiple cells and cell types in native tissues is incomplete due to limitations with current assays. Here, we introduce a multi-layer microfluidic platform (MLTI-Flow) that enables the culture of engineered blood and lymphatic microvessels and independent control of blood, lymphatic, and interstitial fluid pressures. Using optical microscopy methods to measure fluid velocity for applied input pressures, we demonstrate varying rates of interstitial fluid flow as a function of blood, lymphatic, and interstitial pressure, consistent with computational fluid dynamics models. The resulting microfluidic and computational platforms will provide for analysis of key fluid mechanical parameters and cellular mechanisms that contribute to diseases in which fluid imbalances play a role in progression, including lymphedema and solid cancer.

Fluid-Structure Interaction Modelling Predicts That Strain Transfer Through Focal Attachments of Osteoblast Cells are the Primary Mediators of Mechanical Stimulation Under Fluid Flow

2013 ◽  
Author(s):  
T. J. Vaughan ◽  
M. G. Haugh ◽  
L. M. McNamara
Keyword(s):  
Fluid Flow ◽  
Mechanical Stimulation ◽  
Interstitial Fluid ◽  
Bone Cells ◽  
Mechanical Stimulus ◽  
Mechanical Stimuli ◽  
Interstitial Fluid Flow ◽  
Interaction Modelling

Bone continuously adapts its internal structure to accommodate the functional demands of its mechanical environment. It has been proposed that indirect strain-induced flow of interstitial fluid surrounding bone cells may be the primary mediator of mechanical stimuli in-vivo [1]. Due to the practical difficulties in ascertaining whether interstitial fluid flow is indeed the primary mediator of mechanical stimuli in the in vivo environment, much of the evidence supporting this theory has been established through in vitro investigations that have observed cellular activity in response to fluid flow imposed by perfusion chambers [2]. While such in vitro experiments have identified key mechanisms involved in the mechanotransduction process, the exact mechanical stimulus being imparted to cells within a monolayer is unknown [3]. Furthermoreit is not clear whether the mechanical stimulation is comparable between different experimental systems or, more importantly, is representative of physiological loading conditions experienced by bone cells in vivo.

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