Abstract 349: Sall4 Blocks Cardiac Trans-differentiation but Stimulates Cardiac Stem-like Cell (iPSC) Generation and Improve Post MI Function In Vivo

Abstract

Background: Sall4 is an essential component in maintaining embryonic stem cell self-renewal and pluripotency. Given its functional and protein level interaction with cardiac trans-differentiation factors Tbx5/Gata4, as well as its critical role in modulating embryonic cardiac development, we hypothesized that Sall4 may play an important role in cardiac reprogramming. Material/Method: We conducted gain- and loss- of function studies on neonatal and adult cardiac fibroblast from both mouse and rat. We also evaluated Sall4 function on infarcted rat heart. Results: Gata4/Mef2c/Tbx5 (GMT) administration markedly upregulated mRNA expression levels of stem factors including Sall4 , Bmi1 , and p63 , while inhibition of Sall4 largely enhanced GMT- mediated Cardiac troponin T ( cTNT ) induction. Conversely, overexpression of Sall4 plus Gata4/Mef2C in cardiac fibroblast for 7 days induces over 30-fold increase of Oct4 and Nanog by real-time PCR; longer culture induced rapidly-dividing iPSC-like clusters in both neonatal mouse and adult rat cardiac fibroblasts. Further tests showed that these iPSC-like cells were partially positive in alkaline phosphatases staining, capable of forming cardiosphere and differentiating into various cell types. Sall4 delivery also improved post-infarct cardiac function to a level that is comparable with Gata4 in rat. Conclusion: These results suggested that Sall4 is a promising target for cardiac reprogramming even though further characterization in vitro as well as in vivo is needed.