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.

doi:10.1101/2023.03.27.534417

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bioRxiv · 10.1101/2023.03.27.534417

Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing

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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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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.. 2023-03-29. Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing. https://doi.org/10.1101/2023.03.27.534417

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