Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Korea.
Rehabilitation and Regeneration Research Center, CHA University School of Medicine, Seongnam 13488, Korea.
Int J Mol Sci. 2021 Nov 5;22(21):11995. doi: 10.3390/ijms222111995.
Our previous clinical studies demonstrated the synergistic therapeutic effect induced by co-administering recombinant human erythropoietin (rhEPO) in human umbilical cord blood (hUCB) therapy for children with cerebral palsy. However, the cellular mechanism beyond the beneficial effects in this combination therapy still needs to be elucidated. A hypoxic-ischemic encephalopathy (HIE) model of neonates, representing cerebral palsy, was prepared and randomly divided into five groups (hUCB+rhEPO combination, hUCB, and rhEPO treatments over HIE, HIE control, and sham). Seven days after, hUCB was administered intraperitoneally and the rhEPO injections were started. Neurobehavioral tests showed the best outcome in the combination therapy group, while the hUCB and rhEPO alone treatments also showed better outcomes compared with the control ( < 0.05). Inflammatory cytokines were downregulated by the treatments and attenuated most by the combination therapy ( < 0.05). The hUCB+rhEPO treatment also showed remarkable increase in phosphorylation of Akt and potentiation of anti-apoptotic responses with decreased Bax and increased Bcl-2 ( < 0.05). Pre-treatment of MK-2206, an Akt inhibitor, for the combination therapy depressed the anti-apoptotic effects. In conclusion, these findings suggest that the therapeutic effect of hUCB therapy might be potentiated by co-administration of rhEPO via augmentation of anti-inflammatory and anti-apoptotic responses related to the phosphorylation of Akt.
我们之前的临床研究表明，在人脐带血（hUCB）治疗脑瘫儿童的治疗中，联合使用重组人促红细胞生成素（rhEPO）可产生协同治疗效果。然而，这种联合治疗中除了有益效果之外的细胞机制仍需要阐明。我们制备了一个代表脑瘫的新生儿缺氧缺血性脑病（HIE）模型，并将其随机分为五组（hUCB+rhEPO 联合治疗、hUCB 治疗、rhEPO 治疗、HIE 对照组和假手术组）。7 天后，通过腹腔内给予 hUCB，并开始 rhEPO 注射。神经行为学测试显示，联合治疗组的结果最佳，而 hUCB 和 rhEPO 单独治疗组的结果也优于对照组（<0.05）。治疗后炎症细胞因子水平下调，联合治疗组下调最明显（<0.05）。hUCB+rhEPO 治疗还表现出 Akt 磷酸化的显著增加和抗凋亡反应的增强，Bax 减少，Bcl-2 增加（<0.05）。用 Akt 抑制剂 MK-2206 预处理联合治疗会抑制抗凋亡作用。总之，这些发现表明，hUCB 治疗的治疗效果可能通过增强与 Akt 磷酸化相关的抗炎和抗凋亡反应而增强。
