The objective of this CAREER award is to develop efficient bioengineering tools to direct mouse embryonic stem (ES) cells to hematopoietic progenitor cells (HPCs) and ultimately to therapeutic, antigen-specific T cells suitable for immunotherapy and transplantation. In particular, the effects of 3D scaffold structures and various bioreactor cultures on hematopoietic differentiation of ES cells will be studied. Artificial thymus-like environments will be created using microbead-based signaling (synthetic thymic stromal cell) and tetramer-directed antigen presentation (artificial antigen presenting cell) to direct ES cell-derived HPCs into functional T cells. The research objectives, if successful, would lead to the development of scalable methods for generation of hematopoietic stem cells and T cells from ES cells. This could ultimately provide a readily available source for on demandadministration of therapeutic cells in a variety of complex clinical disorders, especially cancers. The educational objectives include community outreach programs for 9th and 10th graders, involving graduate and undergraduate biomedical engineering students and learning scientists from the University of Texas as well as science teachers from area high schools. The PI will also develop challenge-centered teaching modules based on how people learn (HPL) concepts through regular workshops involving high school science teachers and their students.
Stem Cells can be an attractive, alternative source of cells from which functional therapeutic cells can be generated through in vitro differentiation. Such stem cell-derived cells could provide a readily available, on-demand source of transplantable therapeutic cells for several diseases. This project specifically focused on the generation of functional T cells from stem cells. T cells are a type of immune cell that can be used for therapeutic purposes in patients with complex diseases, such as cancer. Currently T cells for such therapies must be isolated from the patient’s peripheral blood, expanded in the laboratory for several weeks, then selected or "trained" for antigen specificity before transplanting them back into the patient. Thus, despite its clinical promise, this approach is constrained by difficulties and inefficiency of patient cell isolation and expansion, associated morbidity, limited availability of donor cells and high cost. In addition, the time required to process patient-isolated cells for therapy can be too long, especially for advanced diseases. Therefore, more practical, clinically relevant technologies for providing efficient, high throughput and on-demand (i.e. readily available) source for antigen-specific, therapeutic T cells are needed. Specifically, during the course of this research, we developed a new bioengineering-based approach that allowed mouse embryonic stem cells or hematopoietic stem cells to be directed towards the T cell lineage using simple, biomaterial-based signaling. We demonstrated that by controlling specific cell signaling pathways we can generate mature T cells that are not only specific for certain antigens, but are also functional. Broadly, the findings from this work resulted in several publications and conference presentations and could lead to new methods for producing therapeutic T cells from stem cells. In addition, the project helped train several graduate and undergraduate students in stem cell and immuno-bioengineering research. Furthermore, as part of a K-12 outreach effort, the project also provided mentoring and scientific training to several high school students.
