Cells respond to mechanical forces in their environment. These forces are likely to be as important to cell phenotype as soluble factors, with similarly complex effects. In particular, mechanical tension generated by cells in response to the stiffness of their environment regulates the behavior of most (if not all) cell types. Over the last ten years, the importance of matrix stiffness as a mechanism for modulating cell shape and function has become increasingly studied, and there is now good evidence that changes in stiffness not only correlate with disease, but contribute to its development. A limitation of most current work studying the role of tissue stiffness in pathology is an exclusive emphasis on cell and tissue elastic modulus, which is frequently reported as a constant independent of time or deformation (strain). Synthetic substrates have been used extensively for studies of the cellular response to substrate stiffness, but have a numberof significant differences from biological tissues: they are linearly elastic, whereas most biologicl materials demonstrate non-linearity~ they fail to incorporate viscosity, although biologicl materials are viscoelastic~ and they are two-dimensional rather than three-dimensional. Thus, while cells clearly respond to changes in the elastic modulus, the impact of viscosity and non-linearity on cells and tissues is not understood even though these factors may be major determinants of cell behavior in mechanically physiological environments. We hypothesize that mechanosensing by cells within tissues or on artificial substrates has characteristic length and time scales and that non-linear elasticity and viscosity are important properties of biological tissues that drive cell behavior and tissue organizaton over both short and long ranges. Our goal is to develop a mechanical model of a tissue, and to determine the biological relevance of various mechanical features to cell behavior and architectural features of this tissue when normal and injured. We will use the normal and fibrotic liver as a model tissue, since there are extensive preliminary characterizations of liver mechanics, although the general principles of our work will be applicable to multiple tissues. We have three specific aims: 1) to carry out a detailed mechanical characterization of the normal and fibrotic liver, and to develop and test a mechanical model of the liver highlighting the relative contributions of cells and the matrix~ 2) to develop and characterize novel viscoelastic substrates that mimic the viscoelasticity of normal and fibrotic livers, and to determine the response of individual cells of the liver to these biologically relevant substrates~ and 3) to computationally model and experimentally test the role of mechanics in large-scale tissue patterning in fibrosis.

Public Health Relevance

Fibrosis, also known as excessive wound healing, is a significant cause of morbidity and mortality worldwide, although there are currently no approved antifibrotic therapies. Our goal is to study the complex mechanical properties of the normal, fibrotic, and cirrhotic liver as a model tissue, to determine the effets of these properties on fibrogenic cells of the liver and on large-scale architectural changes, and to identify interventions affecting these mechanical properties in proof-of-concept studies. This has the potential to significantly increase our understanding of cellular mechanics and fibrosis in general and to identify new diagnostic tests for fibrosis and new classes of antifibroic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB017753-02
Application #
8881175
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Hunziker, Rosemarie
Project Start
2014-07-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ban, Ehsan; Franklin, J Matthew; Nam, Sungmin et al. (2018) Mechanisms of Plastic Deformation in Collagen Networks Induced by Cellular Forces. Biophys J 114:450-461
Gong, Ze; Szczesny, Spencer E; Caliari, Steven R et al. (2018) Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates. Proc Natl Acad Sci U S A 115:E2686-E2695
Embry, Addie E; Liu, Zhenan; Henderson, Joel M et al. (2018) Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models. J Am Soc Nephrol 29:1501-1512
Cao, Xuan; Ban, Ehsan; Baker, Brendon M et al. (2017) Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices. Proc Natl Acad Sci U S A 114:E4549-E4555
Tutwiler, Valerie; Wang, Hailong; Litvinov, Rustem I et al. (2017) Interplay of Platelet Contractility and Elasticity of Fibrin/Erythrocytes in Blood Clot Retraction. Biophys J 112:714-723
Ahmadzadeh, Hossein; Webster, Marie R; Behera, Reeti et al. (2017) Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion. Proc Natl Acad Sci U S A 114:E1617-E1626
Pogoda, Katarzyna; Bucki, Robert; Byfield, Fitzroy J et al. (2017) Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells. Biomacromolecules 18:3040-3051
Zhang, Sijia; Cao, Xuan; Stablow, Alec M et al. (2016) Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction. J Biomech Eng 138:021013
van Oosten, Anne S G; Vahabi, Mahsa; Licup, Albert J et al. (2016) Uncoupling shear and uniaxial elastic moduli of semiflexible biopolymer networks: compression-softening and stretch-stiffening. Sci Rep 6:19270
Cao, Xuan; Moeendarbary, Emad; Isermann, Philipp et al. (2016) A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration. Biophys J 111:1541-1552

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