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Dose Effect of Mesenchymal Stromal Cell Delivery Through Cardiopulmonary Bypass
Kei Kobayashi1, Takuya Maeda1, Mobolanle Ayodeji2
1Department of Cardiac Surgery, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC.
Insights
Mesenchymal stromal cell (MSC) therapy after pediatric cardiac surgery with cardiopulmonary bypass (CPB) is safe and may reduce brain inflammation. High-dose MSCs enhanced neurogenesis in a dose-dependent manner.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Pediatric Cardiology
Background:
- Neurologic impairments are a significant concern for pediatric cardiac surgery survivors.
- Mesenchymal stromal cells (MSCs) show potential in mitigating cardiopulmonary bypass (CPB) effects on neural stem/progenitor cells.
- This study investigates the dose-dependent effects of MSC administration following CPB.
Purpose of the Study:
- To assess the acute dose effects of mesenchymal stromal cells (MSCs) on neural stem/progenitor cells and related biological processes after pediatric cardiopulmonary bypass (CPB).
- To determine the safety and feasibility of varying doses of MSCs delivered during CPB.
- To evaluate the impact of MSCs on neuroinflammation and neurogenesis post-CPB.
Main Methods:
- Twenty piglets were randomized into four groups: control, CPB, CPB with low-dose MSCs, and CPB with high-dose MSCs.
- Assessed cell distribution via MRI, multiorgan function, systemic inflammation markers, microglia activation, and neural stem/progenitor cell activity.
- Utilized magnetic resonance imaging (MRI) to track MSC distribution and assess neurogenic niches.
Main Results:
- High-dose MSC delivery resulted in approximately 10 times greater brain distribution compared to low-dose delivery, with no adverse hemodynamic or biomarker effects.
- Both low and high doses of MSCs normalized microglia activation, reducing cerebral inflammation, and increased neuroblasts in the subventricular zone.
- High-dose MSCs significantly increased the thickness of the active neurogenic area, indicating a dose-dependent effect on the neurogenic niche.
Conclusions:
- Mesenchymal stromal cell (MSC) delivery via cardiopulmonary bypass (CPB) is feasible at doses up to 100 × 10^6 cells/kg.
- MSC treatment can mitigate systemic and cerebral inflammation and modulate the neurogenic niche response to CPB.
- Further research is needed to establish long-term effects and a comprehensive dose-response curve for MSC therapy in this context.
Background:
Neurologic impairments are a significant concern for survivors after pediatric cardiac surgery with cardiopulmonary bypass (CPB). We have previously shown that mesenchymal stromal cell (MSC) delivery through CPB has the potential to mitigate the effects of CPB on neural stem/progenitor cells. This study assessed the dose effects of MSCs.
Methods:
Piglets (n = 20) were randomly assigned to 1 of 4 groups: control, CPB, or CPB followed by MSC administration with low and high doses (10 × 106 and 100 × 106 cells per kilogram). We assessed acute dose effect on cell distribution, multiorgan functions, systemic inflammation, microglia activation, and neural stem/progenitor cell activities.
Results:
By magnetic resonance imaging, approximately 10 times more MSCs were detected within the entire brain after high-dose delivery than after low-dose delivery. No adverse events affecting hemodynamics, various biomarkers, and neuroimaging were detected after high-dose MSC delivery. High-dose MSCs significantly increased circulating levels of interleukin 4 after CPB. Both MSC groups normalized microglia activation after CPB, demonstrating MSC-induced reduction in cerebral inflammation. There was a significant increase in neuroblasts in the subventricular zone in both treatment groups. The thickness of the most active neurogenic area within the subventricular zone was significantly increased after high-dose treatment compared with CPB and low-dose MSCs, suggesting dose-dependent effects on the neurogenic niche.
Conclusions:
MSC delivery through CPB is feasible up to 100 × 106 cells per kilogram. MSC treatment during cardiac surgery has the potential to reduce systemic and cerebral inflammation and to modulate responses of an active neurogenic niche to CPB. Further investigation is necessary to assess the long-term effects and to develop a more complete dose-response curve.
