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Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate

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  • Roshana Thambyrajah

    (Program in Cancer Research. Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC
    Josep Carreras Leukemia Research Institute
    Centro de Investigacion Biomedica en Red (CIBER))

  • Maria Maqueda

    (Program in Cancer Research. Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC)

  • Wen Hao Neo

    (The University of Manchester)

  • Kathleen Imbach

    (Josep Carreras Leukemia Research Institute)

  • Yolanda Guillén

    (Program in Cancer Research. Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC)

  • Daniela Grases

    (Josep Carreras Leukemia Research Institute)

  • Zaki Fadlullah

    (The University of Manchester)

  • Stefano Gambera

    (Molecular Genetics of Angiogenesis Group. Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Francesca Matteini

    (Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL)
    Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia (P-CMR[C]))

  • Xiaonan Wang

    (Wellcome - MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus
    School of Public Health, Shanghai Jiao Tong University, School of Medicine)

  • Fernando J. Calero-Nieto

    (Wellcome - MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus)

  • Manel Esteller

    (Josep Carreras Leukemia Research Institute
    Centro de Investigacion Biomedica en Red (CIBER)
    Institució Catalana de Recerca i Estudis Avançats (ICREA)
    University of Barcelona (UB))

  • Maria Carolina Florian

    (Centro de Investigacion Biomedica en Red (CIBER)
    Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL)
    Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia (P-CMR[C]))

  • Eduard Porta

    (Josep Carreras Leukemia Research Institute)

  • Rui Benedito

    (Molecular Genetics of Angiogenesis Group. Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Berthold Göttgens

    (Wellcome - MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus)

  • Georges Lacaud

    (The University of Manchester)

  • Lluis Espinosa

    (Program in Cancer Research. Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC
    Centro de Investigacion Biomedica en Red (CIBER))

  • Anna Bigas

    (Program in Cancer Research. Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC
    Josep Carreras Leukemia Research Institute
    Centro de Investigacion Biomedica en Red (CIBER))

Abstract

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1 + , HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta.

Suggested Citation

  • Roshana Thambyrajah & Maria Maqueda & Wen Hao Neo & Kathleen Imbach & Yolanda Guillén & Daniela Grases & Zaki Fadlullah & Stefano Gambera & Francesca Matteini & Xiaonan Wang & Fernando J. Calero-Nieto, 2024. "Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45716-y
    DOI: 10.1038/s41467-024-45716-y
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