Engineering Mesenchymal Stem Cells for More Rapid Wound Healing

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

1066585 Dawson Intellectual Merit: Injury to the skin results in the activation of the wound healing process, a complex series of events that includes inflammation, production of granulation tissue, re-epithelialization, and scar tissue formation. Growth factors are essential in mediating the stages of wound healing, which proceed continuously from the time of epidermal damage to scar tissue formation. Elderly patients and patients suffering from chronic illness develop chronic wounds when the wound healing process is arrested in a state of chronic inflammation. Two of the factors that have been associated with the formation of chronic wounds are: (1) impaired production of growth factors and (2) reduced angiogensis. Cell-based therapies, including fibroblasts and mesenchymal stem cells (MSCs), have previously been used to promote more rapid wound healing; however, the effectiveness of these therapies was limited by poor cell migration and engraftment in the wound bed. The proposed studies will focus on the optimization of MSC migration in the wound bed. It is hypothesized that migrating MSCs that disseminate throughout the wound bed will contribute to the formation of granulation tissue, which will constrict the wound for more rapid wound closure. Improved MSC migration may also improve the spatio-temporal activity of the growth factors since they will be secreted from MSCs disseminated throughout the wound tissue. Platelet-secreted soluble proteins, such as PDGF and TGF-?Ò?¡, mediate the migration of bone marrow derived cells to wound tissues; however, little is known about the effects of these proteins on the microscopic mechanical properties of MSCs. Using quantitative real-time microscopy techniques, including particle tracking microrheology and time-lapsed fluorescent microscopy, the effects of PDGF, TGF-?Ò?¡, and/or hypoxia on intracellular rheology, cytoskeletal organization, and interaction with cell adhesion molecules will be monitored. In vitro transwell migration studies will be used to measure the effects of selected stimuli on MSC migration. Together these techniques will be used to determine the mechanical and adhesive properties of migratory MSCs. Optimized MSCs, found to possess the mechanical properties associated with increased migration, will be tested in vivo for migration in the wound bed. MSCs will then be genetically engineered to express vascular endothelial growth factor, which will be used to promote more rapid angiogenesis. The proposed studies will generate fundamental information about the effects of platelet secreted soluble proteins on the mechanical and adhesive properties of MSCs. This information will be utilized in the development of MSC-based therapies for wound healing.