Impact Of Intra-arterial Mesenchymal Stromal Cell Delivery During Pediatric Cardiac Surgery On Systemic And Brain-specific Inflammation In A Juvenile Porcine Model
Takuya Maeda, Kamil Sarkislali, Fahad A. Somaa, Camille Leonetti, Gary R. Stinnett, Zaenab Dhari, Karuna Panchapakesan, Robert Ulrey, Patrick J. Hanley, Richard A. Jonas, Nobuyuki Ishibashi.
Children's National Medical center, Washington, DC, USA.
Objective(s): Cardiopulmonary bypass (CPB) can cause systemic inflammation and prolonged microglia activation in the brain. Mesenchymal stromal cells (MSCs) have significant immunomodulatory properties. We investigated the impact of MSC delivery through CPB on systemic and brain-specific inflammatory responses.
Methods: Two-week old piglets (n=20) were assigned to one of three CPB-induced insults: 1) Control (no insult, n=4); 2) Deep hypothermic circulatory-arrest; (DHCA, n=8) and 3) DHCA followed by 3hrs extra-perfusion (DHCA-L, n=8). CPB-induced insults were amplified in DHCA-L to define the impact of MSCs on extensive inflammation. In two CPB groups, MSCs (10x106 per kg) or saline were administered through CPB during the rewarming period (n=8 each). Multiple-immunoassays determined circulating cytokine/chemokine levels. Microglial number/activation were defined by immunohistochemistry at 3hrs after completion of rewarming. The Spearman correlation coefficient determined the relationship between systemic and neuro-inflammatory responses.
Results: MSC administration increased anti-inflammatory cytokine IL-10 and decreased pro-inflammatory IFN-γ at 20min after the delivery (P<.05). MSC also increased anti-inflammatory cytokine IFN-α at 3hrs after the administration (P<.05). Pro-inflammatory IFN-γ level in DHCA-L was higher than DHCA (P<.05), and MSCs limited this increase (P<.05). Both DHCA groups caused microglia expansion and activation compared with Control (P<.001). MSC treatment reduced CPB-induced microglia expansion and activation (P<.001). Finally microglial number after CPB was inversely correlated with the majority of anti-/intermediate inflammatory cytokines/chemokines (P<.05), indicating a direct relationship between systemic inflammation and microglial expansion after CPB.
Conclusions: MSC delivery through CPB can minimize systemic and neuro-inflammation, thereby potentially reducing neurological impairment in children after cardiac surgery.