人脐带间充质基质细胞作为一种辅助治疗方法与治疗性低体温联合应用于围产期窒息的仔猪模型。

BACKGROUND: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. AIMS: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. METHODS: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 10 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 10 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 10 IN PKH-labeled huMSCs were administered. RESULTS: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. CONCLUSIONS: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 10 cells/kg total dose) based on more rapid aEEG recovery, improved P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h.

背景：在治疗新生儿脑病的治疗性低温（HT）中，残疾率降低，但并非所有婴儿都受益。临床前啮齿动物研究表明间充质基质细胞（MSCs）增强 HT 保护作用。

目的：作者研究了静脉（IV）或鼻内（IN）人脐带衍生 MSC（huMSC）作为 HT 在猪模型中辅助治疗的疗效。

方法：共有 17 只新生仔猪经历短暂的脑缺氧缺血（HI），然后随机分为（i）HI 后 1-13 小时 HT（n=7），（ii）HI 后 24 小时和 48 小时 IV huMSC（30×10 细胞）（n=5）或（iii）HI 后 24 小时和 48 小时 IN huMSC（30×10 细胞）（n=5）。在 30 小时和 72 小时进行磷-31 和氢-1 磁共振光谱（MRS），并定量末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）阳性细胞和少突胶质细胞。在另外两只小猪中，给予 30×10 IN PKH 标记的 huMSC。

结果：各组 HI 严重程度相似。与 HT 相比，HT+IN huMSC 的振幅整合脑电图（aEEG）恢复更快，从 25 小时到 42 小时和 49 小时到 54 小时（P≤0.05）。HT+IN huMSC 组第 2 天 MRS 磷酸肌酸/无机磷高于 HT（P=0.035）。与 HT、HT+IV huMSC 相比，HT+IN huMSC 组海马（P=0.011 和 0.018）、内囊（P=0.013 和 0.037）和脑室周围白质（P=0.15 用于 IN 与 IV huMSC）的 OLIG2 计数增加。与 HT 相比，HT+IN huMSC 组内囊中的 TUNEL 阳性细胞减少（P=0.05）。IN 给药后 12 小时可在脑内检测到 PKH 标记的 huMSC。

结论：与单独 HT 相比，在全脑 HI 后，作者发现 HT+IN huMSC（30×10 细胞/kg 总剂量）在 24 小时和 48 小时给药具有有益作用，基于更快的 aEEG 恢复、改善 P MRS 脑能量代谢和增加 72 小时少突胶质细胞存活。