Transcriptional Determinants of Hemato-Vascular Cell Fate and Plasticity

Recent advances in the reprogramming field have established that somatic cells are more plastic than perceived and can be transcriptionally manipulated to acquire an alternative cell fate. However, the precise regulatory role played by transcription factors (TFs) in regulating distinct cellular programs is not well defined. In our studies, we have determined the discrete roles performed by the hemato-vascular TFs ERG and Fli1 in regulation of physiological vascular homeostasis and in activation of hematopoietic stem cells (HSCs). Combined ERG and Fli1 deletion in endothelium results in acute vasculopathy, due to loss of endothelial cell fate and vascular integrity, hyperinflammation, spontaneous thrombosis and systemic organ failure. ERG and FLI1 deficiency cause transcriptional silencing of pan and organotypic vascular core programs, involved in systemic regulation of inflammation, coagulation, barrier maintenance, and stem cell niche function. Enforced ERG and FLI1 expression in human mesenchymal cells activates vascular programs and functionality. Next, single cell multiome analysis divulged the absence of Fli1 motif from quiescent HSCs. We reveal that Fli1 directs HSC activation programs while manipulating cellular sensory and output machineries, enabling HSPC adoptability with their vascular niches.

During regenerative conditions, Fli1 presets and enables propagation of niche derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli1. Applying FLI1 modified RNA transduction into human lethargic mobilized HSCs, we enabled their vigorous niche mediated expansion and improved engraftment. Thus, basic scientific decryption of cellular programs and their transcriptional regulators offers valuable insights for translational regenerative medicine.