Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing

Tomer Itkin; Sean Houghton; Ryan Schreiner; Yang Lin; Chaitanya R. Badwe; Veronique Voisin; Alex Murison; Negar Seyedhassantehrani; Kerstin B. Kaufmann; Laura Garcia-Prat; Gregory T. Booth; Fuqiang Geng; Ying Liu; Jesus M. Gomez-Salinero; Jae Hung Shieh; David Redmond; Jenny Z. Xiang; Steven Z. Josefowicz; Cole Trapnell; Eric M. Pietras; Joel A. Spencer; Ross Levine; Wenbin Xiao; Lior Zangi; Brandon Hadland; John E. Dick; Stephanie Z. Xie; Shahin Rafii

doi:10.1038/s41590-025-02087-w

Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing

Tomer Itkin^*, Sean Houghton, Ryan Schreiner, Yang Lin, Chaitanya R. Badwe, Veronique Voisin, Alex Murison, Negar Seyedhassantehrani, Kerstin B. Kaufmann, Laura Garcia-Prat, Gregory T. Booth, Fuqiang Geng, Ying Liu, Jesus M. Gomez-Salinero, Jae Hung Shieh, David Redmond, Jenny Z. Xiang, Steven Z. Josefowicz, Cole Trapnell, Eric M. PietrasJoel A. Spencer, Ross Levine, Wenbin Xiao, Lior Zangi, Brandon Hadland, John E. Dick, Stephanie Z. Xie, Shahin Rafii^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e371
Pages (from-to)	378-390
Number of pages	13
Journal	Nature Immunology
Volume	26
Issue number	3
DOIs	https://doi.org/10.1038/s41590-025-02087-w
State	Published - Mar 2025

Funding

Funders	Funder number
Ontario Ministry of Health and Long-Term Care
Hartman Institute for Therapeutic Organ Regeneration
University of California Merced
Starr Foundation
Weill Cornell Medicine
International Development Research Centre
European Hematology Association
Marie-Josée and Henry R. Kravis Center for Molecular Oncology
Cycle for Survival
Ansary Stem Cell Institute
European Molecular Biology Organization
Tel Aviv University’s Sagol Center for Regenerative Medicine and Sheba Medical Center’s Research Authority Startup Funds
Canada Research Chairs
Bristol-Myers Squibb
American Society of Hematology
Princess Margaret Cancer Foundation
Leukemia and Lymphoma Society	R01 DK119394
New York State Stem Cell Science	K08HL140143, RC2DK114777, R01HL168110, NYSTEM-C32596GG
NSF-CREST	NSF-HRD-1547848, P30 CA008748, K08CA267058, R35CA197594, NSF-HRD-2112675
National Cancer Institute	P30 CA08748
Canadian Institutes of Health Research	89932, 154293
Canadian Cancer Society	703212
National Institutes of Health	R35 HL150809, U01AI138329, R01DK136327

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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., ... Rafii, S. (2025). Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing. Nature Immunology, 26(3), 378-390. Article e371. https://doi.org/10.1038/s41590-025-02087-w

@article{7e69bee2fd0643eca046628157aa416e,

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.",

author = "Tomer Itkin and Sean Houghton and Ryan Schreiner and Yang Lin and Badwe, {Chaitanya R.} and Veronique Voisin and Alex Murison and Negar Seyedhassantehrani and Kaufmann, {Kerstin B.} and Laura Garcia-Prat and Booth, {Gregory T.} and Fuqiang Geng and Ying Liu and Gomez-Salinero, {Jesus M.} and Shieh, {Jae Hung} and David Redmond and Xiang, {Jenny Z.} and Josefowicz, {Steven Z.} and Cole Trapnell and Pietras, {Eric M.} and Spencer, {Joel A.} and Ross Levine and Wenbin Xiao and Lior Zangi and Brandon Hadland and Dick, {John E.} and Xie, {Stephanie Z.} and Shahin Rafii",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41590-025-02087-w",

language = "אנגלית",

volume = "26",

pages = "378--390",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Research",

number = "3",

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Itkin, 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, JH, 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 2025, 'Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing', Nature Immunology, vol. 26, no. 3, e371, pp. 378-390. https://doi.org/10.1038/s41590-025-02087-w

TY - JOUR

T1 - Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing

AU - Itkin, Tomer

AU - Houghton, Sean

AU - Schreiner, Ryan

AU - Lin, Yang

AU - Badwe, Chaitanya R.

AU - Voisin, Veronique

AU - Murison, Alex

AU - Seyedhassantehrani, Negar

AU - Kaufmann, Kerstin B.

AU - Garcia-Prat, Laura

AU - Booth, Gregory T.

AU - Geng, Fuqiang

AU - Liu, Ying

AU - Gomez-Salinero, Jesus M.

AU - Shieh, Jae Hung

AU - Redmond, David

AU - Xiang, Jenny Z.

AU - Josefowicz, Steven Z.

AU - Trapnell, Cole

AU - Pietras, Eric M.

AU - Spencer, Joel A.

AU - Levine, Ross

AU - Xiao, Wenbin

AU - Zangi, Lior

AU - Hadland, Brandon

AU - Dick, John E.

AU - Xie, Stephanie Z.

AU - Rafii, Shahin

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

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U2 - 10.1038/s41590-025-02087-w

DO - 10.1038/s41590-025-02087-w

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C2 - 40000903

AN - SCOPUS:85218865976

SN - 1529-2908

VL - 26

SP - 378

EP - 390

JO - Nature Immunology

JF - Nature Immunology

IS - 3

M1 - e371

ER -

Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing

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