Tissue engineering is critical to the delivery of cellular therapies. The discovery of an increasing number of tissue-specific stem cells points to the growing importance of stem cells in organogenesis and thus tissue engineering. Therefore, fundamental understanding of the cellular fate processes that underlie organogenesis originating from tissue-specific cells will prove critical to biological graft engineering and development of cellular therapies. Hematopoietic stem cells (HSCs) are the best known and studied human tissue specific stem cells. HSCs are clinically used through transplantation to rescue myoablated patents via the reconstruction of hematopoietic tissue function originating from the transfused stem cells. HSC transplantation thus represents the clinical use of stem cells and the need to improve graft engineering though fundamental knowledge of stem cell fate processes. The laboratory has made two fundamental discoveries that relate to the migration of CD34+ cells (a surface marker found on immature hematopoietic cells); (A) they extend long (>100 micron) megapods that are highly dynamic and play a role in guiding the migration of these cells; and (B) they spontaneously and rapidly (45 minutes to 2 hours) aggregate in culture in a fashion that is consistent with the secretion of a chemokine. Accordingly, the investigators propose a research program with two specific aims, (1) to determine the molecular makeup of the megapods, in terms of aggregate cytoskeletal elements and surface markers known to play a role in cell-cell communications; and (2) to examine, purify, and identify the chemokine(s) that induce the aggregation process.
Both aims will significantly improve the understanding of the mechanisms that underlies the migration of immature hematopoietic cells. The increasing number of tissue- specific cells that have been described and the similarity in their organogenic functions lead to the expectation that the results of the present proposal are of general importance and interest in stem cell biology, and thus will form the basis for new biological graft engineering.
