Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing Journal Article

  

Authors:	Itkin, T.; Houghton, S.; Schreiner, R.; Lin, Y.; Badwe, C. R.; 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.; Pietras, E. M.; Spencer, J. A.; Levine, R.; Xiao, W.; Zangi, L.; Hadland, B.; Dick, J. E.; Xie, S. Z.; Rafii, S.
Article Title:	Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing
Abstract:	Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
Keywords:	signal transduction; genetics; mouse; animal; cytology; metabolism; animals; mice; mice, knockout; transcription initiation; receptor, notch1; mice, inbred c57bl; c57bl mouse; regeneration; hematopoietic stem cells; hematopoiesis; hematopoietic stem cell; transcription factor fli 1; stem cell niche; transcriptional activation; knockout mouse; proto-oncogene protein c-fli-1; notch1 receptor; humans; human
Journal Title:	Nature Immunology
Volume:	26
Issue:	3
ISSN:	1529-2908
Publisher:	Nature Publishing Group
Date Published:	2025-03-01
Start Page:	378
End Page:	390
Language:	English
DOI:	10.1038/s41590-025-02087-w
PUBMED:	40000903
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85218865976&doi=10.1038%2fs41590-025-02087-w&partnerID=40&md5=46a33eda4f2df2c1f8d7e992e5acb54e
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/223834