RT Journal Article
SR Electronic
T1 Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.19.517153
DO 10.1101/2022.11.19.517153
A1 Cheng, Xiaoyi
A1 Barakat, Radwa
A1 Gorden, Abigail
A1 Snella, Elizabeth
A1 Zhang, Yudi
A1 Dorman, Karin
A1 Fidanza, Antonella
A1 Campbell, Clyde
A1 Espin-Palazon, Raquel
YR 2022
UL http://biorxiv.org/content/early/2022/11/19/2022.11.19.517153.abstract
AB The possibility of specifying functional hematopoietic stem and progenitor cells (HSPCs) from human pluripotent stem cells (hPSCs) would overcome current limitations related to HSPC transplantation. However, generating hPSC-derived HSPCs has been elusive, necessitating a better understanding of the native developmental mechanisms that trigger HSPC specification. Here, we revealed in vivo an intrinsic inflammatory mechanism triggered by Nod1 that drives early hemogenic endothelium (HE) patterning to specify HSPCs. Our genetic and chemical experiments showed that HSPCs failed to specify in the absence of Nod1 and its downstream kinase Ripk2. Rescue experiments demonstrated that Nod1 and Ripk2 acted through NF-kB, and that small Rho GTPases are at the apex of this mechanism. Manipulation of NOD1 in a human system of hPSCs differentiation towards the definitive hematopoietic lineage indicated functional conservation. This work establishes the RAC1-NOD1-RIPK2-NFkB axis as the earliest inflammatory inductor that intrinsically primes the HE for proper HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs for the treatment of blood disorders.HighlightsNod1 specifies HSPCs in vivo through the early induction of hemogenic endothelium.Nod1-Ripk2 controls HSPC specification by activating the inflammatory master TF NF-kB.Nod1 links small Rho GTPases with pro-inflammatory signaling during the genesis of HSPCs.The function of NOD1 is conserved in the development of definitive human HSPCs.Competing Interest StatementThe authors have declared no competing interest.