Institute for Women's Health, University College London, London, UK.
Institute for Women's Health, University College London, London, UK.
Cytotherapy. 2021 Jun;23(6):521-535. doi: 10.1016/j.jcyt.2020.10.005. Epub 2020 Nov 28.
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.
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.
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.
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.
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.
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。
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。
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。
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。
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。
