Fibrous connective tissue provides mechanical support and frameworks for the other tissues of the body. Type 1 collagen is the major protein component of fibrous connective tissue. Fibroblasts are the cell type primarily responsible for collagen biosynthesis and remodeling. As a result of mechanical remodeling, collagen and other components of fibrous connective tissue stretch, slip, and undergo stable reorganization. Such remodeling has been implicated in diverse aspects of normal physiology and pathology including wound repair, fibrosis, scar formation, tumorigenesis, and aging. Matrix remodeling also is an important design feature in tissue engineering. Underlying our research is the premise that we can use 3D collagen matrices to analyze and dissect the structural, functional and mechanical features of fibroblast-matrix interactions in a tissue-like environment. Understanding these features should facilitate discovery of interventions to promote wound repair and enhance development of the field of tissue engineering. Indeed, the general usefulness of 3D matrix models to accelerate a wide range of translational research work increasingly has been recognized. In the current proposal, we plan to analyze human fibroblast migration and collagen flow in nested collagen matrices and in fibrin matrices. We also will analyze human fibroblast migration and clustering on collagen matrices as a function of the growth factor environment and determine if myofibroblasts are migratory cells given appropriate growth factor stimulation. In other studies, the role of cell-cell adherens junctions in cell clustering and cell migration will be assessed. Work on the growth factor environment will focus especially on sphingosine-1-phosphate (S1P), which potentially plays a dual regulatory role -- negative for fibroblast migration and positive for contraction. We will analyze the receptors important for S1P function and analyze the presence of S1P and other promigratory/procontractile factors in acute human wound fluid. Finally, we will test if discoidin domain receptor 2, a cell surface tyrosine kinase receptor that binds collagen, plays a specific role in fibroblast-collagen matrix interactions.

Public Health Relevance

Remodeling of fibrous connective tissue by fibroblasts has been implicated in diverse aspects of normal physiology and pathology including wound repair, fibrosis, scar formation, tumorigenesis, and aging. Matrix remodeling also is an important design feature in tissue engineering. Underlying our research is the premise that we can use 3D collagen matrices containing human fibroblasts to analyze and dissect the structural, functional and mechanical features of connective tissue remodeling in a tissue-like environment. Understanding these features should facilitate discovery of interventions to promote wound repair and enhance development of the field of tissue engineering. Indeed, the general usefulness of 3D matrix models to accelerate a wide range of translational research work increasingly has been recognized.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031321-29
Application #
8245203
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1983-12-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
29
Fiscal Year
2012
Total Cost
$450,668
Indirect Cost
$163,618
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Liu, Zhenan; Ho, Chin-Han; Grinnell, Frederick (2014) The different roles of myosin IIA and myosin IIB in contraction of 3D collagen matrices by human fibroblasts. Exp Cell Res 326:295-306
da Rocha-Azevedo, Bruno; Ho, Chin-Han; Grinnell, Frederick (2013) Fibroblast cluster formation on 3D collagen matrices requires cell contraction dependent fibronectin matrix organization. Exp Cell Res 319:546-55
Grinnell, Frederick; Ho, Chin-Han (2013) The effect of growth factor environment on fibroblast morphological response to substrate stiffness. Biomaterials 34:965-74
Velasquez, Lissette S; Sutherland, Lillian B; Liu, Zhenan et al. (2013) Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc Natl Acad Sci U S A 110:16850-5
da Rocha-Azevedo, Bruno; Grinnell, Frederick (2013) Fibroblast morphogenesis on 3D collagen matrices: the balance between cell clustering and cell migration. Exp Cell Res 319:2440-6
Grinnell, Frederick; Petroll, W Matthew (2010) Cell motility and mechanics in three-dimensional collagen matrices. Annu Rev Cell Dev Biol 26:335-61
Miron-Mendoza, Miguel; Seemann, Joachim; Grinnell, Frederick (2010) The differential regulation of cell motile activity through matrix stiffness and porosity in three dimensional collagen matrices. Biomaterials 31:6425-35
Jiang, Hongmei; Rhee, Sangmyung; Ho, Chin-Han et al. (2008) Distinguishing fibroblast promigratory and procontractile growth factor environments in 3-D collagen matrices. FASEB J 22:2151-60
Miron-Mendoza, Miguel; Seemann, Joachim; Grinnell, Frederick (2008) Collagen fibril flow and tissue translocation coupled to fibroblast migration in 3D collagen matrices. Mol Biol Cell 19:2051-8
Rhee, Sangmyung; Jiang, Hongmei; Ho, Chin-Han et al. (2007) Microtubule function in fibroblast spreading is modulated according to the tension state of cell-matrix interactions. Proc Natl Acad Sci U S A 104:5425-30

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