Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.
Int J Mol Med. 2013 May;31(5):1087-96. doi: 10.3892/ijmm.2013.1290. Epub 2013 Mar 5.
Mesenchymal stem cells (MSCs) have been successfully used for the treatment of experimental intracerebral hemorrhage (ICH). However, the neuroprotective mechanisms through which MSCs improve neurological functional recovery are not fully understood. In the present study, we tested the hypothesis that treatment with MSCs inhibits inflammation after ICH and reduces subsequent brain injury. Adult rats subjected to stereotaxic injection of collagenase VII were transplanted with a subpopulation of human bone marrow-derived MSCs (hBMSCs), termed fetal liver kinase (Flk)-1(+) hBMSCs, or saline into the ipsilateral brain parenchyma 1 day after ICH. Significant recovery of behavior was noted in the Flk-1(+) hBMSC-treated rats beginning 3 days after ICH compared with the control group. Brain water content was significantly decreased in the ipsilateral hemispheres of the Flk-1(+) hBMSC-treated rats when compared with the controls 3 days after ICH. The relative hemorrhage volume was reduced 55 days after Flk-1(+) hBMSC treatment. However, this change was not statistically significant. Flk-1(+) hBMSCs significantly inhibited the proliferation of rat peripheral blood mononuclear cells (rPBMCs) induced in a mixed lymphocyte reaction. Consistently, we found a significant anti-inflammatory effect of Flk-1(+) hBMSCs on the ICH brain, including a decrease in neutrophil infiltration and microglial activation in the peri-ICH area, and downregulation of inflammatory mediators, such as interleukin (IL)-1β, IL-2, IL-4, IL-6, and tumor necrosis factor (TNF)-α. In addition, Flk-1+ hBMSC treatment significantly increased vascular density in the peri-ICH area, and transplanted Flk-1(+) hBMSCs were found to be incorporated into the cerebral vasculature 55 days after transplantation. Overall, these data suggest an essential role for Flk-1(+) hBMSCs in reducing inflammatory infiltration, promoting angiogenesis, and improving functional recovery after ICH in rats.
间充质干细胞（MSCs）已成功用于治疗实验性脑出血（ICH）。然而，MSCs 改善神经功能恢复的神经保护机制尚不完全清楚。在本研究中，我们检验了这样一个假设，即 MSC 治疗可抑制 ICH 后的炎症反应，并减少随后的脑损伤。ICH 后 1 天，将胶原酶 VII 立体定向注射的成年大鼠的骨髓源性 MSC 的一个亚群（称为胎肝激酶（Flk）-1+ hBMSCs）或生理盐水移植到同侧脑实质中。与对照组相比，ICH 后 3 天，Flk-1+ hBMSC 治疗组的大鼠行为明显恢复。ICH 后 3 天，Flk-1+ hBMSC 治疗组同侧半球的脑含水量明显降低。Flk-1+ hBMSC 治疗后 55 天，相对出血体积减少。然而，这一变化没有统计学意义。Flk-1+ hBMSCs 显著抑制混合淋巴细胞反应诱导的大鼠外周血单个核细胞（rPBMCs）的增殖。一致地，我们发现 Flk-1+ hBMSCs 对 ICH 脑具有显著的抗炎作用，包括减少中性粒细胞浸润和 ICH 周围区域的小胶质细胞激活，并下调炎症介质，如白细胞介素（IL）-1β、IL-2、IL-4、IL-6 和肿瘤坏死因子（TNF）-α。此外，Flk-1+ hBMSC 治疗显著增加了 ICH 周围区域的血管密度，并且在移植后 55 天发现移植的 Flk-1+ hBMSCs 整合到脑脉管系统中。总之，这些数据表明 Flk-1+ hBMSCs 在减少炎症浸润、促进血管生成和改善 ICH 后大鼠的功能恢复方面发挥了重要作用。
