SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells

Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and may represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that SCL overexpression accelerates the emergence of hemato-endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryocytic commitment in hESCs. Here, we show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes and platelets in vitro. SCL-overexpressing megakaryocytic cells and their derived platelets respond to different activating stimuli, similarly to their control counterparts. Gene expression profiling of megakaryocytic precursors showed that SCL-overexpression renders a megakaryopoietic molecular signature. The Connectivity Map analysis revealed that trichostatin A (TSA), which is a histone deacetylase (HDAC) inhibitor, functionally mimicked the SCL overexpression-induced effects. Finally, we confirmed that TSA treatment of hESCs promotes the emergence of megakaryocytic precursors. We demonstrated that SCL gain-of-function and HDAC inhibitors are regulators of hESC-derived megakaryocytic cells.