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

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 Fidanza, Clyde A. Campbell and Raquel Espin-Palazon ()
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Xiaoyi Cheng: Iowa State University
Radwa Barakat: Iowa State 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
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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43349-1

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