Mesenchymal stem cells (MSCs) have significant potential as a cell source for cellular therapies. Although the role of many soluble factors and extracellular matrix molecules in MSC differentiation has been examined, the role of cell-cell interactions remains unexplored. This project is based on an innovative research plan to understand the role of cell-cell interactions in stem cell differentiation and to develop novel strategies to tune stem cell fate decisions by controlling the extent of cell-to-cell adhesion. In addition to addressing basic scientific questions, the proposed work will enable design of strategies, biomaterials and devices to control stem cell differentiation with applications in tissue engineering and regenerative medicine and potentially also to cancer. The proposed research will be integrated with educational and outreach activities involving high school students, undergraduate students with emphasis on students from underrepresented minorities, and will incorporate research findings in coursework curricula and in distance-learning modules in a program established by the Department of Biomedical Engineering at the University at Buffalo to provide the New York State industry and graduate students with advanced engineering instruction.
The goal of the proposed work is to employ novel engineering technologies and a multi-prong strategy to improve the understanding of the role of cell-to-cell adhesion in stem cell fate decisions. Differentiation of MSCs is affected by many soluble and insoluble signals in the local microenvironment. In addition to soluble growth factors, cell-extracellular matrix interactions and substrate mechanics have been implicated in stem cell lineage commitment. However, the mechanical and biochemical signals originating from cell-to-cell adhesion remain unexplored in this context. Recent studies implicated adherens junctions in the maintenance of embryonic stem cell self-renewal potential and during cellular reprogramming, but the role of cell-cell interactions in MSC differentiation remains elusive. Therefore, the overarching hypothesis of the proposed work is that cell-to-cell adhesion affects stem cell fate decisions. This hypothesis will be addressed by a series of mechanistic studies to understand the role of Cadherin-11 on MSC differentiation into smooth muscle cells. Methods to be employed include novel microfabrication technologies to control the extent of cell-cell interactions, and the novel lentiviral array (LVA) technology developed in the PI's laboratory to monitor in real time multiple genes and pathways during MSC differentiation. The proposed work represents a significant step forward in understanding the role of cell-to-cell adhesion in stem cell differentiation and will enable design of strategies, biomaterials and devices for applications in tissue engineering and regenerative medicine. Finally, although the proposed work will focus on MSCs, the research findings are expected to impact other types of stem cells, such as cancer stem cells, where intercellular interactions may also play an important role.
