Dampened Reactive Hematopoiesis and Systemic Inflammatory Response Following Early Recurrent Myocardial Infarction in Mice

Acute myocardial infarction (AMI) impacts the regenerative capacity of hematopoietic stem and progenitor cells (HSPCs) following injury, but it remains unclear if these functional alterations persist beyond the initial ischemic event.A minimally invasive mouse model of recurrent myocardial infarction was established using echocardiography-guided coronary interventions. Bone marrow HSPCs were quantified and analyzed for proliferation by flow cytometry and BrdU incorporation. Peripheral blood leukocytes and inflammatory cytokines (IL-6, G-CSF) were measured by flow cytometry and ELISA. Bone marrow extracellular TGF-β1 was assessed by ELISA, and its functional role was evaluated through antibody-mediated inhibition.The minimally invasive infarction model was validated through electrocardiography, cardiac biomarkers, echocardiography, and cardiac pathology staining. Fourteen days post-I/R or sham treatment, bone marrow hematopoiesis returned to a steady state with no significant differences in Lin-Sca-1+c-Kit+ (LSK), hematopoietic stem cell (HSC), multipotent progenitor (MPP), and granulocyte/macrophage progenitor (GMP) cell numbers. However, after a secondary ischemic challenge, there was a dampened reactive hematopoiesis indicated by reduced HSPCs, compared to the first ischemic event. BrdU incorporation analysis showed decreased HSPC proliferation activity during the reparative phase after initial ischemic challenge, linking dampened hematopoiesis to decreased HSPCs proliferation. Additionally, early recurrent infarct mice had fewer neutrophils released in peripheral blood and lower serum IL-6 and G-CSF levels. Elevated TGF-β1 levels were detected in bone marrow extracellular fluid during the reparative phase of cardiac-ischemic injury, and inhibiting TGF-β1 reversed the dampened reactive hematopoiesis of HSPCs in an early recurrent MI setting.Our data suggest that initial myocardial ischemia challenges blunt bone marrow reactive hematopoiesis to subsequent ischemic stress, with decreased HSPC proliferation contributing to diminished regenerative capacity. TGF-β1 in bone marrow extracellular fluid may mediate this decreased HSPC proliferation.