scholarly journals Matrix stiffness and shear stresses modulate hepatocyte functions in a fibrotic liver sinusoidal model

2020 ◽  
Author(s):  
Wang Li ◽  
Peiwen Li ◽  
Ning Li ◽  
Yu Du ◽  
ShouQin Lü ◽  
...  
Keyword(s):  
Blood Flow ◽  
Liver Fibrosis ◽  
Porous Membrane ◽  
Shear Stresses ◽  
Matrix Stiffness ◽  
Collagen Gels ◽  
Liver Sinusoidal Endothelial Cells ◽  
Fibrotic Liver ◽  
Sinusoidal Model ◽  
Cell Behaviors

Extracellular matrix rigidity has important effects on cell behaviors and is increased sharply during liver fibrosis and cirrhosis. Hepatic blood flow is essential in maintaining hepatocytes (HC) functions. However, it is still unclear how matrix stiffness and shear stresses orchestrate HC phenotype in concert. A fibrotic 3D liver sinusoidal model is constructed using a porous membrane sandwiched between two PDMS layers with respective flow channels. The HC are cultured in collagen gels of various stiffness in the lower channel, while the upper channel is pre-seeded with liver sinusoidal endothelial cells (LSEC) and accessible to shear flow. The results reveal that HC cultured within stiffer matrices exhibit less albumin production and cytochrome P450 (CYP450) reductase expression. Low shear stresses enhance synthetic and metabolic functions of HC, while high shear stresses lead to the loss of HC phenotype. Furthermore, both two mechanical factors regulate HC functions in a cooperative way by complementing with each other. These observations are likely attributed to mechanically-induced mass transport or key signaling molecule of hepatocyte nuclear factor 4 alpha (HNF4α). Present results provide an insight in understanding the mechanisms of HC dysfunction in liver fibrosis and cirrhosis especially from viewpoint of matrix stiffness and blood flow.

scholarly journals SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Vaishaali Natarajan ◽  
Edward N. Harris ◽  
Srivatsan Kidambi
Keyword(s):  
Endothelial Cells ◽  
Liver Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Protein Profile ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells ◽  
Fibrotic Liver ◽  
Nonalcoholic Fatty Liver ◽  
Functional Features

Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.

Multiscale Modeling of Flow Induced Thrombogenicity Using Dissipative Particle Dynamics and Molecular Dynamics

2013 ◽  
Author(s):  
Danny Bluestein ◽  
João S. Soares ◽  
Peng Zhang ◽  
Chao Gao ◽  
Seetha Pothapragada ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Blood Flow ◽  
Red Blood Cells ◽  
Platelet Activation ◽  
Blood Cells ◽  
Dissipative Particle Dynamics ◽  
Particle Dynamics ◽  
Coagulation Cascade ◽  
Shear Stresses ◽  
Activated Platelets

The coagulation cascade of blood may be initiated by flow induced platelet activation, which prompts clot formation in prosthetic cardiovascular devices and arterial disease processes. While platelet activation may be induced by biochemical agonists, shear stresses arising from pathological flow patterns enhance the propensity of platelets to activate and initiate the intrinsic pathway of coagulation, leading to thrombosis. Upon activation platelets undergo complex biochemical and morphological changes: organelles are centralized, membrane glycoproteins undergo conformational changes, and adhesive pseudopods are extended. Activated platelets polymerize fibrinogen into a fibrin network that enmeshes red blood cells. Activated platelets also cross-talk and aggregate to form thrombi. Current numerical simulations to model this complex process mostly treat blood as a continuum and solve the Navier-Stokes equations governing blood flow, coupled with diffusion-convection-reaction equations. It requires various complex constitutive relations or simplifying assumptions, and is limited to μm level scales. However, molecular mechanisms governing platelet shape change upon activation and their effect on rheological properties can be in the nm level scales. To address this challenge, a multiscale approach which departs from continuum approaches, may offer an effective means to bridge the gap between macroscopic flow and cellular scales. Molecular dynamics (MD) and dissipative particle dynamics (DPD) methods have been employed in recent years to simulate complex processes at the molecular scales, and various viscous fluids at low-to-high Reynolds numbers at mesoscopic scales. Such particle methods possess important properties at the mesoscopic scale: complex fluids with heterogeneous particles can be modeled, allowing the simulation of processes which are otherwise very difficult to solve by continuum approaches. It is becoming a powerful tool for simulating complex blood flow, red blood cells interactions, and platelet-mediated thrombosis involving platelet activation, aggregation, and adhesion.

Possible Therapeutic Uses of Extracellular Vesicles for Reversion of Activated Hepatic Stellate Cells: Context and Future Perspectives

2021 ◽  
Vol 21 ◽  
Author(s):  
Fahim Rejanur Tasin ◽  
Debasish Halder ◽  
Chanchal Mandal
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Target Cells ◽  
Fibrotic Liver ◽  
Paracrine Effects ◽  
Cell Therapies

: Liver fibrosis is one of the leading causes for cirrhotic liver disease and the lack of therapies to treat fibrotic liver is a major concern. Liver fibrosis is mainly occurred by activation of hepatic stellate cells and some stem cell therapies had previously reported for treatment. However, due to some problems with cell-based treatment, a safe therapeutic agent is vehemently sought by the researchers. Extracellular vesicles are cell-derived nanoparticles that are employed in several therapeutic approaches, including fibrosis, for their ability to transfer specific molecules in the target cells. In this review the possibilities of extracellular vesicles to inactivate stellate cells are summarized and discussed. According to several studies, extracellular vesicles from different sources can either put beneficial or detrimental effects by regulating the activation of stellate cells. Therefore, targeting extracellular vesicles for maximizing or inhibiting their production is a potential approach for fibrotic liver treatment. Extracellular vesicles from different cells can also inactivate stellate cells by carrying out the paracrine effects of those cells, working as the agents. They are also implicated as smart carrier of anti-fibrotic molecules when their respective parent cells are engineered to produce specific stellate cell-regulating substances. A number of studies showed stellate cell activation can be regulated by up/downregulation of specific proteins, and extracellular vesicle-based therapies can be an effective move to exploit these mechanisms. In conclusion, EVs are advantageous nano-carriers with the potential to treat fibrotic liver by inactivating activated stellate cells by various mechanisms.

scholarly journals Mesenchymal stem cells attenuate liver fibrosis by targeting Ly6Chi/lo macrophages through activating the cytokine-paracrine and apoptotic pathways

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuan-hui Li ◽  
Shuang Shen ◽  
Tong Shao ◽  
Meng-ting Jin ◽  
Dong-dong Fan ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Apoptotic Bodies ◽  
Chronic Injury ◽  
Apoptotic Pathway ◽  
Fibrotic Liver ◽  
Apoptotic Pathways ◽  
Regulatory Functions ◽  
Cell Inhibition

AbstractMesenchymal stem cell (MSC) therapy has become a promising treatment for liver fibrosis due to its predominant immunomodulatory performance in hepatic stellate cell inhibition and fibrosis resolution. However, the cellular and molecular mechanisms underlying these processes remain limited. In the present study, we provide insights into the functional role of bone marrow-derived MSCs (BM-MSCs) in alleviating liver fibrosis by targeting intrahepatic Ly6Chi and Ly6Clo macrophage subsets in a mouse model. Upon chronic injury, the Ly6Chi subset was significantly increased in the inflamed liver. Transplantation of BM-MSCs markedly promoted a phenotypic switch from pro-fibrotic Ly6Chi subset to restorative Ly6Clo subpopulation by secreting paracrine cytokines IL-4 and IL-10 from the BM-MSCs. The Ly6Chi/Ly6Clo subset switch significantly blocked the source of fibrogenic TGF-β, PDGF, TNF-α, and IL-1β cytokines from Ly6Chi macrophages. Unexpectedly, BM-MSCs experienced severe apoptosis and produced substantial apoptotic bodies in the fibrotic liver during the 72 h period of transplantation. Most apoptotic bodies were engulfed by Ly6Clo macrophages, and this engulfment robustly triggered MMP12 expression for fibrosis resolution through the PtdSer-MerTK-ERK signaling pathway. This paper is the first to show previously unrecognized dual regulatory functions of BM-MSCs in attenuating hepatic fibrosis by promoting Ly6Chi/Ly6Clo subset conversion and Ly6Clo macrophage restoration through secreting antifibrogenic-cytokines and activating the apoptotic pathway.

The Effects of Geometry and Static Boundary Conditions on Microvessel Outgrowth in a 3D Model of Angiogenesis

2010 ◽  
Author(s):  
Clayton J. Underwood ◽  
Laxminarayanan Krishnan ◽  
Lowell T. Edgar ◽  
Steve Maas ◽  
James B. Hoying ◽  
...  
Keyword(s):  
Boundary Condition ◽  
Boundary Conditions ◽  
Direct Relationship ◽  
3D Model ◽  
Mechanical Strain ◽  
Matrix Stiffness ◽  
Collagen Gels ◽  
3D Collagen ◽  
In Vitro Angiogenesis

We reported previously that, in addition to mechanical strain, a constrained boundary condition alone can alter the organization of microvessel outgrowth during in vitro angiogenesis [1]. After 6 days of culture in vitro, microvessels aligned parallel to the long axis of rectangular 3D collagen gels that had constrained edges on the ends. However, unconstrained cultures did not show any alignment of microvessels. The ability to direct microvessel outgrowth during angiogenesis has significant implications for engineering prevascularized grafts and tissues in vitro, therefore an understanding of this process is important. Since there is direct relationship between the ability of endothelial cells to contract 3D gels and matrix stiffness [2], we hypothesize that some constrained boundary conditions will increase the apparent matrix stiffness and in turn will limit gel contraction, prevent microvessel alignment, and reduce microvessel outgrowth. The objective of this study was to compare microvessel growth and alignment under several different static boundary conditions.

Numerical study of hemodynamics after stent implantation during the cardiac cycle

2021 ◽  
Vol 15 (2) ◽  
pp. 8016-8028
Author(s):  
Abdelhakem Belaghit ◽  
B. Aour ◽  
M. Larabi ◽  
A. A. Tadjeddine ◽  
S. Mebarki
Keyword(s):  
Blood Flow ◽  
Stent Implantation ◽  
Cardiac Cycle ◽  
Numerical Study ◽  
Shear Stresses ◽  
Flow Profile ◽  
Hemodynamic State ◽  
Dynamics Simulations ◽  
Medical Planning

The descending aortic aneurysm is one of the most catastrophic cardiovascular emergencies resulting in high mortality worldwide. Clinical observations have pointed out that stent implantation in the sick aorta should probably allow stabilization of the hemodynamic state of the patient's aorta. To better understand the hemodynamic impact of a stent-treated aneurysm, numerical simulations are used to evaluate hemodynamic parameters. These latter including flow profile, velocity distribution, aortic wall pressure and shear stress, which are difficult to measure in vivo. It should be noted that the numerical modeling assists in medical planning by providing patterns of blood circulation, in particular, the distribution of pressures and shear stresses in the wall. In this context, the pulsatile blood flow in the aneurysmal aorta with stent is studied by CFD (Computational Fluid Dynamics) simulations. Realistic boundary conditions time dependent are prescribed at the level of the different arteries of the complete aorta models. The hemodynamic profile of the aneurysmal aorta with stent was analyzed by contour planes of velocity vectors, pressures and shear stresses at different times during the cardiac cycle. The obtained results made it possible to show the effect of the stent on the improvement of the blood flow by solving the problems of hemodynamic disturbances in the aorta.  The methodology used in this work has revealed detailed and necessary information for the cases studied and shows the interest of the numerical tool for diagnosis and surgery.

Stiffness is associated with hepatic stellate cell heterogeneity during liver fibrosis

2021 ◽  
Author(s):  
Enis Kostallari ◽  
Bo Wei ◽  
Delphine Sicard ◽  
Jiahui Li ◽  
Shawna A. Cooper ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Focal Adhesion ◽  
Hepatic Stellate Cell ◽  
Stellate Cell ◽  
Liver Stiffness ◽  
Specific Protein ◽  
Cellular Level ◽  
Fibrotic Liver ◽  
Soft Matrix

The fibrogenic wound-healing response in liver increases stiffness. Stiffness mechano-transduction in turn amplifies fibrogenesis. Here, we aimed to understand the distribution of stiffness in fibrotic liver, how it impacts hepatic stellate cell (HSC) heterogeneity and identify mechanisms by which stiffness amplifies fibrogenic responses. Magnetic resonance elastography and atomic force microscopy demonstrated a heterogenous distribution of liver stiffness at macroscopic and microscopic levels, respectively, in a carbon tetrachloride (CCl4) mouse model of liver fibrosis as compared to controls. High stiffness was mainly attributed to extracellular matrix dense areas. To identify a stiffness-sensitive HSC sub-population, we performed scRNA-seq on primary HSCs derived from healthy versus CCl4-treated mice. A sub-cluster of HSCs was matrix-associated with the most upregulated pathway in this sub-population being focal adhesion signaling, including a specific protein termed four and a half LIM domains protein 2 (FHL2). In vitro, FHL2 expression was increased in primary human HSCs cultured on stiff matrix as compared to HSCs on soft matrix. Moreover, FHL2 knockdown inhibited fibronectin and collagen 1 expression, whereas its overexpression promoted matrix production. In summary, we demonstrate stiffness heterogeneity at the whole organ, lobular, and cellular level which drives an amplification loop of fibrogenesis through specific focal adhesion molecular pathways.

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