Department 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.
Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC.
Ann Thorac Surg. 2023 Dec;116(6):1337-1345. doi: 10.1016/j.athoracsur.2022.07.035. Epub 2022 Aug 8.
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.
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 × 10 and 100 × 10 cells per kilogram). We assessed acute dose effect on cell distribution, multiorgan functions, systemic inflammation, microglia activation, and neural stem/progenitor cell activities.
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.
MSC delivery through CPB is feasible up to 100 × 10 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.
心肺转流（CPB）后儿科心脏手术后的神经功能障碍是幸存者的一个重大关注点。我们之前已经表明，CPB 中递送间充质基质细胞（MSC）具有减轻 CPB 对神经干细胞/祖细胞影响的潜力。本研究评估了 MSC 的剂量效应。
小猪（n=20）被随机分配到以下 4 组之一：对照组、CPB 组或 CPB 后接受低剂量（10×10 个细胞/千克）和高剂量（100×10 个细胞/千克）MSC 给药的组。我们评估了急性剂量对细胞分布、多器官功能、全身炎症、小胶质细胞激活和神经干细胞/祖细胞活性的影响。
通过磁共振成像，高剂量给药后，整个大脑中检测到的 MSC 数量大约是低剂量给药后的 10 倍。高剂量 MSC 给药后，没有发现影响血流动力学、各种生物标志物和神经影像学的不良事件。CPB 后，高剂量 MSC 组显著增加了白细胞介素 4 的循环水平。两组 MSC 均使 CPB 后小胶质细胞激活正常化，表明 MSC 诱导减少了脑炎症。两个治疗组的侧脑室下区的神经母细胞数量均增加。与 CPB 和低剂量 MSC 相比，高剂量治疗组侧脑室下区最活跃的神经生成区的厚度显著增加，提示剂量依赖性影响神经生成龛。
CPB 中递送 MSC 可达 100×10 个细胞/千克是可行的。心脏手术期间的 MSC 治疗有可能减轻全身和脑炎症，并调节活跃的神经生成龛对 CPB 的反应。需要进一步研究以评估长期效果并开发更完整的剂量反应曲线。
