Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN-γ Signaling

Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn(-/-) HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn(-/-) HSPCs are enriched for gene sets related to interferon gamma (IFN-gamma) signaling. Hemgn(-/-) HSPCs show enhanced responses to IFN-gamma treatment and increased aging over time. Blocking IFN-gamma signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn(-/-) HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-gamma-treated Hemgn(-/-) mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-gamma signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation.

Automated summary

Hemgn plays a critical regulatory role in the engraftment and reconstitution of HSPCs by negatively regulating IFN-γ signaling. Hemgn(-/-) HSPCs show defective engraftment during transplantation, which is associated with IFN-γ signaling, and the defect can be rescued by intervention in IFN-γ signaling. Hemgn deficiency sustains nuclear Stat1 tyrosine phosphorylation via suppressing TC45 activity.