Suppression of the Prostaglandin I2-Type 1 Interferon Axis Induces Extramedullary Hematopoiesis to Promote Cardiac Repair After Myocardial Infarction.

Abstract

BACKGROUND Immune cells are closely associated with all processes of cardiac repair after myocardial infarction (MI), including the initiation, development, and resolution of inflammation. Spleen extramedullary hematopoiesis (EMH) serves as a crucial source of emergency mature blood cells that are generated through the self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs). However, how EMH responds to MI and the role of EMH in cardiac repair after MI remains unclear. METHODS To assess the role of spleen EMH in MI, a Tcf21CreER Scfflox/flox MI mouse model with inhibited EMH was constructed. GFP+ (green fluorescent protein) hematopoietic stem cells were sorted from eGFP (enhanced green fluorescent protein) mouse spleen by flow cytometry and injected into Tcf21CreER Scfflox/flox mice to test the sources of local inflammatory cells during MI. Using highly specific liquid chromatography-tandem mass spectrometry and single-cell RNA sequencing, we analyzed the lipidomic profile of arachidonic acid metabolites and the transcriptomes of HSPCs in the spleen after MI. RESULTS We found that MI enhanced EMH, as reflected by the increase in spleen weight and volume and the number of HSPCs in the spleen. The lack of EMH in Scf-deficient mice exacerbated tissue injury after MI. Analysis of the transcriptome of spleen HSPCs after MI revealed that the type 1 interferon pathway was substantially inhibited in hematopoietic stem cell/multipotent progenitor subclusters, and the absence of type 1 interferon signaling enhanced the MI-induced spleen EMH. Lipidomics analysis revealed that prostaglandin I2 (PGI2) was markedly reduced in the spleen. PGI2 suppressed MI-induced EMH through a PGI2 receptor (IP)-cyclic adenosine monophosphate-453p-SP1 cascade in spleen HSPCs. Hematopoietic cell-specific IP-deficient mice exhibited enhanced EMH and improved cardiac recovery after MI. CONCLUSIONS Together, our findings revealed that a PGI2-IFN axis was involved in spleen EMH after MI, providing new mechanistic insights into spleen EMH after MI and offering a new therapeutic target for treating ischemic cardiac injury.