Abstract
Introduction: Precise comprehension of the cardio-spleen-bone-marrow immune cells axis is crucial to understanding the changes occurring during diabetes (DM) pathogenesis. This study aims to investigate the alterations in immune cell kinetics in DM after myocardial infarction (MI). Methods: MI was induced in DM and healthy control using C57BL/N6 mice. Animals were sacrificed at D1, D3, D7, & D28 post-MI to obtain their heart, peripheral blood (PB), spleen, and bone marrow (BM) and then each organ cell suspension was isolated, and analyzed by flow cytometry. EPC-colony-forming assay (EPC-CFA) was performed using BM, PB, and spleen-derived MNCs. Results: Findings demonstrated that despite the normal production of BM, CD45+ cells are decreased at D1-D3 in spleen and PB of DM’s. Further analysis depicted that total and pro-inflammatory neutrophil (N1) decreased at D1-D3 in PB and spleen at D3-D7 in DM mice, suggesting that DM causes spleen's neutrophil alterations that cannot compensate for PB and ischemia tissue demand. Infiltrated macrophages (total, M1, M2) decreased at D3 in DM-ischemic heart. Total and M1 (D1-D3) and M2 (D3-D7) notably decreased in DM-PB than control group, showing impaired macrophage recruitment/polarization in DM. Moreover, heart myeloid dendritic cells (mDCs) increased from D1-D7, the latter enhanced recruitment of CD8 cells increase from D1 to D28 in DM-infarcted-myocardium. The total CD4 cells decreased at D1-D3 in DM-PB, indicating a delayed adaptive immune response to MI. The B-cells diminished at D1-D3 in PB, at D3 in myocardium, and D7 in spleen, indicating impaired mobilization of those cells from bone marrow to compensate. EPC-CFA demonstrated dramatically decrease of definitive EPC colonies in spleen and BM from D1-D28 in DM mice vs control in vitro , indicating that DM significantly impairs EPC colony-forming bioactivity by limiting EPCs' differentiation from primitive to definitive. Conclusion: Our study highlights significant alterations of cardio-spleno-bone-marrow immune cells axis following MI in DM animals, revealing delayed innate/adaptive immune responses and impaired differentiation of EPCs.
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