INTELLECTUAL MERIT: Using synthetic materials to engineer artificial cell microenvironments that recapitulate the essential characteristics of their in vivo counterparts to guide stem cell fate selection has become an important strategy in regenerative medicine. However, it remains a challenge to create materials that mimic dynamic presentation of insoluble ligands, limiting the ability to control and study stem cell fate selection in well-defined biomimetic cell microenvironments. The goal of the project is to develop a method to engineer dynamic biomaterials that enable reversible and orthogonal regulation of multiple insoluble ligands to cell surface receptors without exposing cells to the soluble counterparts of the ligands and to use such engineered materials to study mesodermal differentiation of human induced pluripotent stem cells (iPSCs) in cell microenvironments presenting dynamically controlled integrin ligands as a model system. The specific objectives of this proposal are: (1) design, preparation, and physical-chemical characterization of substrates capable of presenting multiple insoluble ligands reversibly and orthogonally, (2) investigation of reversible and orthogonal regulation of cell-accessible and cell-inaccessible states of the insoluble ligands, (3) investigation of mesodermal differentiation of human iPSCs toward myocardial and hemato-endothelial progenitors in response to dynamically modulated ligands for two specific integrins. Completion of this project will bridge the gap between the need for understanding and controlling stem cell fate selection in response to dynamically modulated insoluble ligands and the lack of enabling dynamic biomaterials. Multifunctional dynamic biomaterials based on this method will allow creation of cell microenvironments that better emulate their in vivo counterparts. These biomimetic artificial cell microenvironments will not only guide more efficient stem cell differentiation toward desired lineages for cell-based therapy, but also enable the study of fundamentals of developmental biology in well-controlled systems, which is difficult to access with animal studies.
BROADER IMPACTS: The approach developed in this project can be adapted for dynamic modulation of many insoluble ligands of interest to construct a variety of biomimetic cell microenvironments. Study and control of cell behavior, fate selection, and functions in these engineered systems will have implications for both technological development and fundamental understandings. The proposed education activities, aimed at creation of a qualified and diversified workforce in the biomaterials and tissue engineering fields, will be completely integrated with the PI's research interests. The PI will give hands-on demonstrations of smart biomaterials (glucose-sensitive gels, temperature-responsive materials for engineering cell sheets, hydrogels allowing cell encapsulation), a seminar on smart biomaterials, and summer research opportunities to the students in the Minneapolis Public Schools High Tech Girls Society and the Exploring Careers in Engineering and Physical Science programs. She will promote the research activities of underrepresented minority and women undergraduate students through participation in the North Star STEM program, and she will help to establish a strong Biomaterials and Tissue Engineering track in the Biomedical Engineering curriculum at the University of Minnesota.