Cancer Biology, Surgery
Keck School of Medicine
The Saban Research Institute
Childrens Hospital Los Angeles
- Cell Cycle
- Growth & Proliferation
- Signal Transduction
- Developmental Biology
Research OverviewWound Repair and Regeneration
The long-term goal of my research is to elucidate the cellular and molecular basis of excess scar formation during tissue repair. Tissue repair recapitulates processes in embryonic morphogenesis and developmental tissue regeneration. It is accomplished through concerted events involving various cell types, extracellular matrix (ECM) components, cytokines, and other soluble mediators such as proteases and their inhibitors. Due to the complex nature of the repair process and lack of a proper model system, information regarding the molecular mechanism underlying the dynamic interactions and feedback controls among participating components during wound repair is very limited. Two in vitro 3- dimensional matrix culture systems have been established in my laboratory: the In Vitro Fibroplasia Model and Modified Skin Composite Model. These models feature key characteristics of skin wound repair and provide several important benefits over other in vitro systems.
Using the model system, multiple effects of transforming growth factor-beta (TGF-�) on tissue repair, i.e., ECM reorganization, degradation, and synthesis were demonstrated. In addition, it was uncovered that fibroblasts isolated from keloid fibrotic lesions exhibit a defect in fibrin degradation which is caused by an increase in the level of cellular plasminogen activator inhibitor 1 (PAI-1) and a concomitant decrease in the level of urokinase plasminogen activator (uPA). The plasmin activation system is central to matrix remodeling since it not only regulates fibrin degradation, but also influences TGF-� and collagenase activities. Conversely, TGF-� stimulates production of PAI-1 and collagen.
We have also recently discovered a developmental switch in the balance between PA and PAI-1 toward PAI-1 increase during a transition from mouse fetal skin scarless wound healing (E15 and E16) to healing with scars (after E17) (Island et al., 1999). Therefore, our working hypothesis is that the developmental switch in the balance between PA and PAI-1 toward PAI-1 increase results in scar formation in skin wound healing.
Furthermore, the excessive PAI-1 expression in skin fibroblasts of keloid (a developmentally deranged skin condition) attributes to keloid fibrosis. Both the in vitro (skin model systems) and in vivo (normal, TGF-�3 null, and Msx-2 null mouse models) wounding approaches are taken to investigate the cellular and molecular mechanisms underlying scar formation and tissue fibrosis.