Our goal for this award was to determine how various genes contribute to inherent differences between cells made in vivo (tissue) versus in vitro (from pluripotent stem cells). Our previous work identified a number of genes that always appeared to be expressed differently between cells made in different contexts. For pluripotent stem cells and their progeny to be useful clinically, it is imperative that the cells generated be as close as possible to their tissue derived counterparts. Therefore, in the last year we have begun to experimentally turn some of these genes on or off depending on their variance with cells found in tissue. We have have found that some of these manipulations do indeed bring these cells closer together, while others seem to have no effect. In the coming year, we are going to combine those manipulations that are effective to see if they can have an additive or perhaps even a synergistic effect. We aim to eventually create cells in vitro that perfectly mimic those found in tissue and develop methods to make this process universally applicable across cell types to facilitate both disease modeling and regenerative medicine.