Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing
Itkin, T.; Houghton, S.; Schreiner, R.; Lin, Y.; Badwe, C.; Voisin, V.; Murison, A.; Seyedhassantehrani, N.; Kaufmann, K. B.; Garcia-Prat, L.; Booth, G. T.; Geng, F.; Liu, Y.; Gomez-Salinero, J. M.; Shieh, J.-H.; Redmond, D.; Xiang, J. Z.; Josefowicz, S. Z.; Trapnell, C.; Spencer, J. A.; Zangi, L.; Hadland, B.; Dick, J. E.; Xie, S. Z.; Rafii, S.
Show abstract
Transition between activation and quiescence programs in hematopoietic stem and progenitor cells (HSC/HSPCs) is perceived to be governed intrinsically and by microenvironmental co-adaptation. However, HSC programs dictating both transition and adaptability, remain poorly defined. Single cell multiome analysis divulging differential transcriptional activity between distinct HSPC states, indicated for the exclusive absence of Fli-1 motif from quiescent HSCs. We reveal that Fli-1 activity is essential for HSCs during regenerative hematopoiesis. Fli-1 directs activation programs while manipulating cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche. During regenerative conditions, Fli-1 presets and enables propagation of niche-derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli-1. Applying FLI-1 modified-mRNA transduction into lethargic adult human mobilized HSPCs, enables their vigorous niche-mediated expansion along with superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immune regenerative medicine.
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