Abstract 22: CXCR4 Expression on Endogenous Bone Marrow Stem/Progenitor Cells is Crucial for Preservation of Myocardial Function After MI

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Background: Studies examining the role of bone marrow CXCR4 in the response to myocardial infarction (MI) using the CXCR4 antagonist AMD3100 in animal myocardial infarction (MI) models are inconclusive. Chronic AMD3100 administration exacerbated injury and myocardial dysfunction while bolus injection immediately post-MI reduced size of the injury with improvement of systolic function.

Aims: As MI mobilizes bone marrow stem/progenitor cells and immune cells into peripheral blood which then home to injured myocardium to facilitate and impair, respectively, regeneration and healing we were interested in the role of bone marrow CXCR4 on functional recovery, angiogenesis, and cardiomyogenesis.

Experimental Approach: To define the role of CXCR4 in the bone marrow we generated chimeras with bone marrow from CXCR4flox/flox mice. Wild type mice were transplanted with CXCR4flox/flox or CXCR4flox/flox UBQ Cre bone marrow cells after a lethal dose of irradiation. CXCR4 deletion was induced 5 weeks after transplant with Tamoxifen. The coronary artery was ligated after another two weeks. Function was evaluated five weeks post MI function by echo and pathology analysis was performed to measure scar size, collagen content, hypertrophy, capillary counts, CSCs counts, angiogenesis and cardiomyogenesis.

Results: compared to wild type, mice with CXCR4 KO bone marrow had impaired LV systolic function evaluated 5 weeks post-MI by echocardiography. Morphometric analysis of Masson’s Trichrome stained sections confirmed LV exacerbated chamber enlargement (expansion index), larger scar and decreased infarcted wall thickness in mice with bone marrow cells deficient for CXCR4. More detailed analysis revealed c-kit positive CSC numbers were decreased as were proliferating c-kit CSC indicated by Ki67 staining. Decreased proliferation also correlated with reduced numbers of newly formed myocytes (αsarcomeric actinpos/BrdUpos). Capillary and arteriole counts were also reduced in infarcted hearts of mice with CXCR4 KO bone marrow compared to wild type.

Conclusion: based on these findings we can conclude that CXCR4 is necessary for bone marrow cell homing to infarcted myocardium to preserve LV function, regenerate lost myocardium, and promote angiogenesis.

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