1033 - Translating human development to new therapies with pluripotent stem cells

Abstract

Human pluripotent stem cells (hPSCs) represent a novel cell source for developing new therapies to treat a broad spectrum of diseases including those of the hematopoietic and cardiovascular systems. The development of such therapies is, however, dependent on our ability to generate the appropriate cell type in the differentiation cultures. To be able to reproducibly produce therapeutically relevant target cell populations in high purity, it is essential to understand their developmental origin and the regulatory pathways that control their specification. To address this issue, we set out to map the onset of human hematopoietic and cardiovascular development using the hPSC model. Using developmental biology guided approaches, we demonstrated that key decisions are made early in both the hematopoietic and cardiovascular differentiation cultures. We showed that primitive and definitive hematopoiesis develop from distinct KDR+ mesoderm populations that can be distinguished based on expression of glycophorin A (CD235a). Additionally, we found that the induction of these mesoderm subtypes is regulated by Wnt and Nodal/activin signaling and that through appropriate manipulation of these pathways, it is possible to generate populations enriched in either primitive or definitive hematopoiesis. Similarly, our studies on cardiovascular development revealed that the major cardiomyocyte subtypes, ventricular and atrial arise from distinct mesoderm populations that are also distinguished by CD235a expression. The induction of these mesoderm subpopulations was found to be regulated by different levels of activin and BMP signaling. By staged manipulation of these pathway agonists it is possible to produce highly enriched populations of either ventricular or atrial cardiomyocytes. Collectively, the findings from these studies highlight the importance of defining and characterizing the early developmental events that control lineage determination for the production of specific cell types from hPSCs. The therapeutic applications of these hPSC-derived populations will be discussed.