Human embryonic stem (hES) cells offer a potentially unlimited source of replacement cells for treating human degenerative diseases such as cardiovascular disease, macular degeneration, diabetes, Parkinson's disease, Alzheimers, as well as wound healing and spinal cord injury to name a few. In addition, advances in reprogramming somatic cells (induced pluripotent stem (iPS) cells) are a potential future source of patient specific pluripotent cells. Near term, these recent advances will no doubt increase the number of research grade ES-like cell lines dramatically and thus increase the market for research tools to identify, track and isolate progenitors of differentiated cell types of therapeutic interest. The directed differentiation of pluripotent stem cells to a desired differentiated cell type is generally inefficient often yielding only a few percent of the starting cells. Moreover, hES cells are difficult to grow on a large scale. Thus there is a need for reagents that identify progenitors of useful cell types that can be isolated and expanded before differentiation to allow cost effective scale up and increase the yield of differentiated product. Moreover, such reagents would be valuable research reagents for basic stem cell research and developmental biology. We propose here to develop a novel technology platform called time-lapse phage display for identifying progenitor cell binding peptides for use as tools to target, track, and isolate progenitors of therapeutically useful cells. In phase 1, we will test the feasibility of the technology by isolating peptides that target progenitors of CD31 (PECAM1) positive cells of endothelial lineage that we will derive from hES cells (NIH registered line WA09). The resulting peptides will be characterized for specificity and used to trace the lineage of the targeted progenitor cells. In phase II, we will use the technology to identify peptides for additional progenitors primarily of cardiovascular as well as other lineages. The use of the peptides for cell tracking and isolation will be optimized. Near term revenue will be generated through the commercialization of the peptides as reagents such as conjugated fluorescent probes and kits for progenitor identification, cell lineage tracking, and cell isolation. Selected peptides will be used internally to develop regenerative therapies of interest to ACT such as ischemic and cardiovascular disease and other peptides will be commercialized by licensing to corporate partners. We anticipate the technology proposed here will be generally applicable for identifying peptides that target progenitors derived from hES cells as well as other types of pluripotent or multipotent stem cells including induced iPS and adult stem cells.
Public Health Relevance: Human embryonic stem (hES) cells provide a potentially unlimited source of pluripotent cells for treating human injury and disease because of their ability to continually self renew as well as differentiate into virtually any mature cell type. Additional sources of ES-like cells from reprogrammed adult cells may soon prove to be more cost-effective and less restrictive than their embryonic counterparts. However, regardless of the source of pluripotent cells, a key problem remains of how to obtain commercial quantities of clinical grade cells for transplantation. Moreover the optimal cells for transplantation in most cases have yet to be determined. We propose to address these issues by developing tools to identify, track, and isolate progenitor cells derived from pluripotent hES cells. We will initially use a novel peptide selection method called time-lapse phage display to identify peptides that target progenitors of human vascular cells and characterize the peptides for cell-specific targeting, cell isolation, and their ability to track the progenitors as they differentiate. The long term goals are to apply the proposed technology to identifying progenitors of cardiovascular and other cell lineages for therapeutic development and to commercialize the resulting cell targeting reagents, cell tracking and cell isolation kits.
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