Background

The objective of this study was to systematically review the literature to determine the effect of combined hypothermia (HTH) and mesenchymal stem cell (MSC) therapy (administered during or immediately before or after HTH) compared with HTH alone on brain injury and neurobehavioural outcomes in animal models of neonatal hypoxic–ischaemic encephalopathy.

Methods

Primary outcomes assessed were neuropathological measures and neurobehavioural measures of brain outcome. Secondary outcomes were brain protein proinflammatory cytokine status. Risk of bias (ROB) was assessed with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) ROB assessment tool.

Results

Of 393 studies identified, 3 studies in postnatal day 7 (P7) male Sprague–Dawley rats met the inclusion criteria. Meta-analyses were undertaken for neuropathological measures (apoptotic cells, astrocytes, microglia), neurobehavioral measures (rotarod test and negative geotaxis), and proinflammatory cytokine levels. Two of the three studies scored low or unclear ROB across all measures. Treatment with HTH-MSCs together significantly improved astrocyte optical density by standardised mean difference (SMD) of 0.71 [95% confidence interval (CI) −1.14, −0.28]. No other measures showed significant differences.

Conclusions

There is insufficient preclinical data to confirm the efficacy of combined HTH-MSC therapy over HTH alone. Future studies should utilise a reporting checklist such as in SYRCLE or Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines to improve reporting standards.

Impact

• Very few articles investigating the use of MSCs for the treatment of hypoxic–ischaemic encephalopathy are clinically relevant.

• Continuing to publish studies in models of hypoxic–ischaemic encephalopathy without the inclusion of HTH therapy does not progress the field towards improved clinical outcomes.

• This study shows that HTH and MSC therapy improves measures of astrogliosis.

• More studies are required to establish the efficacy of HTH and MSCs on measures of neuropathology and neurobehavior.

• The reporting of preclinical data in this space could be improved by using reporting checklists such as the SYRCLE or ARRIVE tools.

中文翻译：

---

新生儿缺氧缺血性脑病动物模型中联合低温和间充质干细胞：系统评价

背景

本研究的目的是系统回顾文献以确定联合低温 (HTH) 和间充质干细胞 (MSC) 治疗（在 HTH 期间或之前或之后立即给药）与单独 HTH 相比对脑损伤和神经行为结果的影响新生儿缺氧缺血性脑病动物模型。

方法

评估的主要结果是神经病理学测量和大脑结果的神经行为测量。次要结果是脑蛋白促炎细胞因子状态。使用实验室动物实验系统审查中心 (SYRCLE) ROB 评估工具评估偏倚风险 (ROB)。

结果

在确定的 393 项研究中，3 项针对出生后第 7 天 (P7) 雄性 Sprague-Dawley 大鼠的研究符合纳入标准。对神经病理学测量（凋亡细胞、星形胶质细胞、小胶质细胞）、神经行为测量（旋转棒试验和负趋地性）和促炎细胞因子水平进行了荟萃分析。三项研究中有两项在所有测量中的 ROB 得分较低或不清楚。与 HTH-MSCs 一起治疗显着提高了星形胶质细胞的光密度，标准化平均差 (SMD) 为 0.71 [95% 置信区间 (CI) -1.14, -0.28]。没有其他措施显示出显着差异。

结论

没有足够的临床前数据来证实 HTH-MSC 联合治疗优于单独 HTH 的疗效。未来的研究应使用报告清单，例如 SYRCLE 或动物研究：体内实验报告 (ARRIVE) 指南，以改进报告标准。

影响

• 很少有研究使用 MSCs 治疗缺氧缺血性脑病的文章具有临床相关性。

• 在不包括 HTH 治疗的情况下继续发表缺氧缺血性脑病模型的研究并不能使该领域朝着改善临床结果的方向发展。

• 该研究表明，HTH 和 MSC 治疗可改善星形胶质细胞增生的测量。

• 需要更多的研究来确定 HTH 和 MSCs 在测量神经病理学和神经行为方面的功效。

• 可以通过使用 SYRCLE 或 ARRIVE 工具等报告清单来改进该领域临床前数据的报告。