The long term goal of this research is to understand the cell biology of wound healing, particularly granulation tissue formation and its replacement by neodermis, wound contracture, and re-epithelialization. During the next four years, we plan to systematically investigate several in vitro model systems and to carry out related in vivo studies. The reorganization of hydrated collagen gels by human fibroblasts will be studied to learn the identity of the serum and cell-secreted factors necessary for gel reorganization to occur. Also, the effects of exogenous matrix components on fibroblast migration and gel reorganization will be determined. Human keratinocyte migration and differentiation on reorganized collagen will be analyzed; and we will determine whether fibronectin receptor function is initiated under these culture conditions. The ability of fibroblasts and keratinocytes in the collagen gels to phagocytize collagen and fibrin debris will be measured. An in vitro model mimicking cutaneous wounds will be established by culturing keratinocytes on top of hydrated collagen gels that contain fibroblasts, and placing a plasma clot into a physical defect prepared in the gels. The migration of cells with respect to the """"""""wound"""""""" interface will be determined, and the possibility that a granulation-like tissue is formed will be analyzed by studying morphological and biosynthetic features of the cells. Throughout the above studies, we will use anti-fibronectin antibodies and fibronectin cell binding region-peptide fragments to determine fibronectin function. Finally, in vivo experiments will be carried out to extend the in vitro findings. In particular, we will try to assess fibronectin function in granulation tissue formation and re-epithelialization, fibronectin receptor initiation in migrating keratinocytes, and possible differences between freshly isolated and cultured keratinocytes in their abilities to form grafts on full-thickness wounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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da Rocha-Azevedo, Bruno; Ho, Chin-Han; Grinnell, Frederick (2015) PDGF?stimulated dispersal of cell clusters and disruption of fibronectin matrix on three-dimensional collagen matrices requires matrix metalloproteinase-2. Mol Biol Cell 26:1098-105
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
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; Ho, Chin-Han (2013) The effect of growth factor environment on fibroblast morphological response to substrate stiffness. Biomaterials 34:965-74
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
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
Rhee, Sangmyung; Ho, Chin-Han; Grinnell, Frederick (2010) Promigratory and procontractile growth factor environments differentially regulate cell morphogenesis. Exp Cell Res 316:232-44
Grinnell, Frederick; Petroll, W Matthew (2010) Cell motility and mechanics in three-dimensional collagen matrices. Annu Rev Cell Dev Biol 26:335-61
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

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