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 Tcf21 CreER Scf flox/flox MI mouse model with inhibited EMH was constructed. GFP + (green fluorescent protein) hematopoietic stem cells were sorted from eGFP (enhanced GFP) mouse spleen by flow cytometry and injected into Tcf21 CreER Scf flox/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– 453 p-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.