Author:
Itkin Tomer,Houghton Sean,Schreiner Ryan,Lin Yang,Badwe Chaitanya R.,Voisin Veronique,Murison Alex,Seyedhassantehrani Negar,Kaufmann Kerstin B.,Garcia-Prat Laura,Booth Gregory T.,Geng Fuqiang,Liu Ying,Gomez-Salinero Jesus M.,Shieh Jae-Hung,Redmond David,Xiang Jenny Z.,Josefowicz Steven Z.,Trapnell Cole,Spencer Joel A.,Zangi Lior,Hadland Brandon,Dick John E.,Xie Stephanie Z.,Rafii Shahin
Abstract
AbstractTransition 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.
Publisher
Cold Spring Harbor Laboratory