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TRANSLATIONAL PHYSIOLOGY

Improvement in cardiac function after bone marrow cell thearpy is associated with an increase in myocardial inflammation

Division of Cardiac Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

Submitted 11 June 2008 ; accepted in final form 12 November 2008

The mechanisms for the beneficial impact of bone marrow cell (BMC) therapy after myocardial infarction (MI) are ill defined. We hypothesized that the implanted cells improve function by attenuating post-MI inflammation and repair. In mice, 3 x 10⁵ fresh BMCs were implanted immediately after coronary ligation. Cardiac function was evaluated over time. Inflammatory cytokines and cells were measured, and their impacts on the (myo)fibroblastic repair response, angiogenesis, and scar formation were determined. All differences below had P values of <0.05. BMC implantation reduced the decline in fractional shortening and ventricular dilation. Invasive hemodynamics confirmed a difference in systolic function at day 7 and diastolic function at day 28 favoring the BMC group. Interestingly, BMC implantation caused a 1.6-fold increase in the number of macrophages infiltrating the infarct but did not affect neutrophils. This increase was associated with a 1.9-fold higher myocardial TNF- level. The heightened inflammatory response was associated with a 1.4-fold induction of transforming growth factor-β and a 1.3-fold induction of basic fibroblast growth factor. These changes resulted in a 1.6-fold increase in -smooth muscle actin and a 1.9-fold increase in total discoidin domain receptor 2-expressing cells in the BMC group. These two markers are expressed by cardiac (myo)fibroblasts. Capillary density in the border zone increased 2.0-fold. Consistent with a more robust repair-mediated scar "contracture," the final scar size was 0.7-fold smaller in the BMC group. In conclusion, after MI, BMC therapy induced a more robust inflammatory response that improved the "priming" of the (myo)fibroblast repair phase. Enhancing this response may further improve the beneficial impact of cellular therapy.

cell transplantation; myocardial infarction; cell therapy; myofibroblasts

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