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Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases

Author

Listed:
  • Xiaoyi Cheng

    (Iowa State University)

  • Radwa Barakat

    (Iowa State University
    Benha University)

  • Giulia Pavani

    (Children’s Hospital of Philadelphia)

  • Masuma Khatun Usha

    (Iowa State University)

  • Rodolfo Calderon

    (Iowa State University)

  • Elizabeth Snella

    (Iowa State University)

  • Abigail Gorden

    (Iowa State University)

  • Yudi Zhang

    (Iowa State University)

  • Paul Gadue

    (Children’s Hospital of Philadelphia)

  • Deborah L. French

    (Children’s Hospital of Philadelphia)

  • Karin S. Dorman

    (Iowa State University
    Iowa State University)

  • Antonella Fidanza

    (Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh)

  • Clyde A. Campbell

    (Iowa State University)

  • Raquel Espin-Palazon

    (Iowa State University)

Abstract

Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)-derived HSPCs and their derivatives has been elusive, necessitating a better understanding of the developmental mechanisms that trigger HSPC specification. Here, we reveal that early activation of the Nod1-Ripk2-NF-kB inflammatory pathway in endothelial cells (ECs) primes them to switch fate towards definitive hemogenic endothelium, a pre-requisite to specify HSPCs. Our genetic and chemical embryonic models show that HSPCs fail to specify in the absence of Nod1 and its downstream kinase Ripk2 due to a failure on hemogenic endothelial (HE) programming, and that small Rho GTPases coordinate the activation of this pathway. Manipulation of NOD1 in a human system of definitive hematopoietic differentiation indicates functional conservation. This work establishes the RAC1-NOD1-RIPK2-NF-kB axis as a critical intrinsic inductor that primes ECs prior to HE fate switch and HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs and their derivatives for the treatment of blood disorders.

Suggested Citation

  • Xiaoyi Cheng & Radwa Barakat & Giulia Pavani & Masuma Khatun Usha & Rodolfo Calderon & Elizabeth Snella & Abigail Gorden & Yudi Zhang & Paul Gadue & Deborah L. French & Karin S. Dorman & Antonella Fid, 2023. "Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43349-1
    DOI: 10.1038/s41467-023-43349-1
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