Introduction: Neurodevelopmental impairment is emerging as one the most important current challenges for survivors after pediatric cardiac surgery. Cardiopulmonary bypass (CPB) can cause substantial systemic inflammation and trigger prolonged microglial activation in the brain. Mesenchymal stem/stromal cells (MSCs) have significant immunomodulatory properties and regulate microglia activation. We hypothesize that intra-arterial MSC delivery through CPB is neuroprotective by modulating systemic and brain-specific inflammatory responses.
Methods: Two-week old piglets (n=12) were randomly assigned to one of 3 groups: (1) Control, (2) Deep hypothermic circulatory arrest (DHCA), (3) DHCA followed by MSC administration. In group 3, superparamagnetic iron oxide (SPIO)-labeled MSCs (10 x 106 per kg) were delivered through the aortic cannula during the rewarming period. Animals were sacrificed 3hrs after CPB. Distribution of MSCs was examined with MRI and immunohistochemistry. Plasma cytokine/chemokine levels were determined by multiplex immunoassay. Iba1 and CD11b were used to define CPB-induced microglial activation. Clinically-relevant physiological biomarkers determined the effect of MSC delivery on multi-organ functions after cardiac surgery.
Results: T2* weighted MRI showed diffuse distribution of hypointense voxels (SPIO particles) throughout the entire brain with large clusters along the lateral and third ventricles. Immunohistochemistry also revealed an even distribution of SPIOs within the cortex (50.93%) and white matter (49.07%). We have demonstrated an increase in permeability of the blood-brain barrier after DHCA. Consistently we identified SPIOs located in the extra-vascular space. MSC delivery through CPB modulated plasma cytokine/chemokine expression after surgery. In the brain MSC treatment reduced microglia expansion and activation resulting from CPB. Various biomarkers after MSC delivery did not differ compared with CPB group. No evidence of either embolic events or microstrokes were observed by MRI and histology.
Conclusion: MSC delivery during CPB is highly effective and shows translational potential to minimize CPB-induced systemic inflammation and microglial activation in children with CHD.