Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.

TitleTranscriptional activation of regenerative hematopoiesis via microenvironmental sensing.
Publication TypeJournal Article
Year of Publication2025
AuthorsItkin T, Houghton S, Schreiner R, Lin Y, Badwe CR, Voisin V, Murison A, Seyedhassantehrani N, Kaufmann KB, Garcia-Prat L, Booth GT, Geng F, Liu Y, Gomez-Salinero JM, Shieh J-H, Redmond D, Xiang JZ, Josefowicz SZ, Trapnell C, Pietras EM, Spencer JA, Levine R, Xiao W, Zangi L, Hadland B, Dick JE, Xie SZ, Rafii S
JournalNat Immunol
Volume26
Issue3
Pagination378-390
Date Published2025 Mar
ISSN1529-2916
KeywordsAnimals, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Protein c-fli-1, Receptor, Notch1, Regeneration, Signal Transduction, Stem Cell Niche, Transcriptional Activation
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.

DOI10.1038/s41590-025-02087-w
Alternate JournalNat Immunol
PubMed ID40000903
PubMed Central ID5510238
Grant ListK08 CA267058 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P50 CA254838 / CA / NCI NIH HHS / United States

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