The two major pluripotent cells in mouse, embryonic stem cells (mESCs) and epiblast stem cells (EpiSCs) are supported by distinct signal inputs, which enhances the self-renewal potential and enables reversible switching between the two pluripotent states. Although expression profiles of key regulatory factors accumulate in each state or transition states, the link between signals and underlying gene regulatory networks remains unsolved. Recent observations from single cell analyses show that uncoordinated and discrete molecular transitions cause reversible switching between self-renewal and lineage-affiliated states until final commitment to a specific lineage. Based on the mining of collective expression data and the novel definition of pluripotent cell populations, we are aiming to develop a new framework to simulate and predict the population-level state-transitions connected with signal inputs while considering single cell heterogeneity. The model will also predict how the pluripotent populations are sustained and the gene regulatory mechanism of irreversible loss of self-renewal potential.

In adults, the beating heart cells (cardiomyocytes) cannot divide to regenerate the injured or diseased heart; instead they are replaced by a non-beating scar. In several clinical studies, injected cells from the bone marrow or skeletal muscle into the heart have resulted in, at best, modest functional improvement. In all cases, transplanted cell survival has been poor indicating that any beneficial effect is likely to be transient and mediated via mechanisms associated with secreted factors. A major limitation in the development of cellular therapies to the heart is cell survival and integration post transplantation. Therefore, we have developed a model system capable of screening for cell survival and integration into engineered heart tissue (EHT). Our in vitro model system will enable the rapid and efficient screening of candidate cell types and survival / integration factors for pre-clinical studies. Currently, initial studies focus on the survival and integration of embryonic stem cell (ESC)-derived cardiac cells and progenitors into EHT. Our ESC-derived cardiac cells are fluorescently labeled in order to quantitatively track the injected cells into EHT. Once the system is developed, we are planning to pursue screening for factors (small molecules, cytokines) that increase cell survival and integration into cardiac tissue in a high through-put manner.