Short summary of research projects:
Laminin extracellular matrix in skin biology and diseases (Figure 1):
In all tissues studied, the family of proteins known as laminins have been shown to be major effectors of cell adhesion and spreading. Laminins are major components of the extracellular matrix (ECM) in the basement membrane zone (BMZ) and influence a variety of important biological processes including cell attachment, migration, angiogenesis, wound healing and tissue development. Human diseases involving laminins clearly illustrate the important functions that these molecules provide. For example the absence of laminin-211 (previously called laminin-2) causes a type of severe muscular dystrophy, the defect of laminin-332 (also called laminin-5) leads to a severe and often life-threatening blistering disorder. Our laboratory uses advanced cellular, molecular biology techniques and animal models to study the functions of two newly identified laminin-411 and laminin-511 in epithelial pathobiological processes, including blood vessel formation (angiogenesis), wound healing, aging and tumor invasion.
Laminins in angiogenesis:
We have found that endothelial (blood vessel) cells produce two laminin proteins, laminin-411 and laminin-511. These two laminins may play critical roles in promoting adhesion and spreading of endothelial cells and cells which come in contact with them including tumor cells and inflammation cells. We have found that both laminin-411 and laminin-511 have strong effects on cell attachment, migration and capillary tubule formation of human skin microvascular endothelial cells. These functions are mediated by beta 1 and alpha v integrin receptors and regulated by various matrix metalloproteinases (MMPs). Blocking the expression of these two laminins could inhibit endothelial cell function and angiogenesis. As we continue our studies, we expect to understand more of these extracellular matrix molecules and their contributions in the angiogenesis and hence in wound repair, skin aging and cancer.
Laminins in skin tumor development and angiogenesis (Figure 2):
It has recently been appreciated that the aggressive invasive behavior of malignant tumor cells is related to the extracellular environment. We are currently studying the function of laminin-511 in melanomas and squamous cell carcinomas (SCC), which are two most common malignancies of human skin cancers. Importantly, we have identified a high expression of laminin-511 in human malignant melanomas while there is no expression detected in benign nevi. Significant higher expression of laminin-511 was also detected in invasive SCC mass and tumor-associated vasculature. Furthermore, a close correlation of laminin-511 expression level and SCC clinical stages was observed. Knockdown the expression of laminin-511 with RNA interfering technique could significantly inhibit tumor cell migration and invasion in cell culture and tumor growth in animal models. Additionally, knockdown of laminin-511 expression could block endothelial cell function and tumor angiogenesis. These findings suggest a key role of laminin-511 in the development of these tumors and a potential biomarker for the tumor early diagnosis and a target for the therapy.
Microenvironment regulation of adipose derived stem cells in wound repair:
Recent studies have shown that adipose derived stem cells (ADSCs) improve the repair of various organs. However, the mechanisms underlying ADSC differentiation in wounds remain unclear. This is in part due to the lack of human models or lack of lineage tracking in clinical trials since vast majority of studies examined human or mouse ADSCs injected into animals. The ability of ADSCs to differentiate into both mesenchymal and non-mesenchymal cell types and their relative ease to isolate and expand in culture make them a promising agent for cell-based therapy. However, the lack of understanding of ADSC in tissue repair will hinder its applications in the clinic. Our long range goal is to improve the therapeutic outcomes for wound patients, especially chronic wounds. We are currently studying the contribution of ADSCs in wound angiogenesis and repair using a human skin xenograft model. We are to determine the fate of locally delivered human ADSCs during wound healing in human skin grafts, and to determine if enrichment of wound microenvironment with chemokines and extracellular matrix components may increase efficacy of ADSC therapy for wound healing.