Role of Nonmuscle Myosin II in Hepatic Stellate Cell Activation
1 online resource (171 pages) : PDF
University of North Carolina at Charlotte
The hepatic stellate cell (HSC) plays a pivotal role in the development of hepatic fibrosis. Regulation of liver microcirculation is a complex system where blood flow is under systemic and sinusoidal control. Upon a fibrogenic stimulus, quiescent HSCs transdifferentiates into activated myofibroblast-like cell and exert a sustained contractile force, resulting in hyperconstricted vessels. Early phenotypic changes observed during the transdifferentiation process include cell stretching and elongation of cytoplasmic processes. These changes facilitate proliferation and migration of HSCs to the areas of injury where excess amounts of collagen are deposited altering normal liver architecture and leading to liver dysfunction. Under chronic liver injury, this wound healing response perpetuates and impairs blood flow through the liver resulting in portal hypertension, which is one of the main clinical manifestations of liver fibrosis. Nonmuscle myosin II (NMM II) has been shown to be involved in cellular contraction, proliferation and migration. Using a whole-cell contraction assay and a selective myosin II inhibitor, we have demonstrated that myosin II is essential for HSC contraction. Additionally, the expression of NMM II isoforms in activated HSCs was upregulated. To further explore the mechanism of regulation, we altered in vitro conditions to more closely depict the in vivo environment using a matrix stiffness assay. Under these conditions, a minimal increase in NMM II-A and II-B mRNA expression was detected, which suggests that mechanical properties of the liver may regulate NMM II isoforms in HSCs. siRNA mediated isoform knockdown had no effect on culture-activated HSC contraction and proliferation but cell migration was inhibited by 25%. Overall, our results demonstrate that myosin II isoforms play a critical role in the development of portal hypertension and HSC migration; however, the specific isoform responsible for this hypercontractile response has yet to be identified.
FIBROSISHEPATIC STELLATE CELLLIVERNONMUSCLE MYOSIN IIPORTAL HYPERTENSION
McKillop, IainDreau, DidierYengo, ChristopherLangford, David
Thesis (Ph.D.)--University of North Carolina at Charlotte, 2009.
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