Identifying hMSC interaction pathways in soluble interferon-gamma and stratified collagen/heparin coatings for the manufacturing of therapeutic cells

点击翻译按钮获取中文摘要

Human mesenchymal stromal cells (hMSC) show promise for treating deadly incurable diseases. One of the main limitations of hMSC production is the growth of fully functional cells in bioreactors. Treatment with interferon gamma (IFN) enhances the therapeutic potency of hMSCs but also inhibits growth. Coating hMSCs with layers of collagen (COL) and heparin (HEP) reduces the inhibition while maintaining the therapeutic enhancement, but it is unknown how the layers cause this to occur. This project will identify the specific pathways by which COL/HEP coatings enhance hMSC response to IFN. This knowledge will support the design of optimal bioreactor platforms for the manufacturing of highly therapeutic cells. Students from underrepresented populations will engage in research at the interface between engineering and biology. This will help develop a strong and diverse biomanufacturing workforce.The central hypothesis of this project is that COL/HEP coatings work synergistically with soluble IFN to modulate signaling pathways regulating proliferation and immunosuppressive properties. This hypothesis was formulated, in large part, based on preliminary data indicating that COL/HEP coatings: induce expression of basic fibroblast growth factor (FGF2) and reduce the anti-proliferative effect of IFN while enhancing immunomodulatory cytokine secretion. The specific objectives are: (1) To establish the relationship between the coatings and the activation of the FGF2 pathway in hMSCs, and its relation to proliferation; (2) To establish the mechanism by which IFN activates hMSCs cultured on COL/HEP coatings; and (3) To determine the extent to which COL/HEP coatings remain consistent when translated to microcarriers for suspension-based bioreactors. This project will directly impact the cell manufacturing field by merging polymeric materials with biochemical signals to produce a technology that enhances hMSCs activation and therapeutic potency.This project is jointly funded by the Cellular and Biochemical Engineering Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.