Background and Purpose. Previously, we found that insulin-like growth factor-1 (IGF-1) levels in the infarct cortex in the acute phase of distal middle cerebral artery occlusion (dMCAO) rats are increased by intravenous infusion of allogeneic mesenchymal stem/stromal cells (MSCs). CD68+ microglia and NeuN+ neurons are part, but not all, of the sources of IGF-1. The present study is aimed at exploring the respective contributions of brain endogenous Iba-1+ microglia, GFAP+ astrocytes, infiltrated neutrophils, lymphocytes and monocytes/macrophages, and peripheral circulation, to the increased IGF-1 level in the infarct cortex after MSC infusion. Materials and Methods. Ischemic brain injury was induced by dMCAO in Sprague-Dawley rats. The transplantation group received MSC infusion 1 h after dMCAO. Expression of IGF-1 in GFAP+ astrocytes, Iba-1+ microglia/macrophages, CD3+ lymphocytes, Ly6C+ monocytes/macrophages, and neutrophil elastase (NE)+ neutrophils was examined to determine the contribution of these cells to the increase of IGF-1. ELISA was performed to examine IGF-1 levels in blood plasma at days 2, 4, and 7 after ischemia onset. Results. In total, only 5-6% of Iba-1+ microglia were colabeled with IGF-1 in the infarct cortex, corpus callosum, and striatum at day 2 post-dMCAO. MSC transplantation did not lead to a higher proportion of Iba-1+ cells that coexpressed IGF-1. In the infarct cortex, all Iba-1+/IGF-1+ double-positive cells were also positive for CD68. In the infarct, corpus callosum, and striatum, the majority (50-80%) of GFAP+ cells were colabeled with ramified IGF-1 signals. The number of GFAP+/IGF-1+ cells was further increased following MSC treatment. In the infarct cortex, approximately 15% of IGF-1+ cells were double-positive for CD3. MSC treatment reduced the number of infiltrated CD3+/IGF-1+ cells by 70%. In the infarct, few Ly6C+ monocytes/macrophages or NE+ neutrophils expressed IGF-1, and MSC treatment did not induce a higher percentage of these cells that coexpressed IGF-1. The IGF-1 level in peripheral blood plasma was significantly higher in the MSC group than in the ischemia control group. Conclusion. The MSC-mediated increase in IGF-1 levels in the infarct cortex mainly derives from two sources, astrocytes in brain and blood plasma in periphery. Manipulating the IGF-1 level in the peripheral circulation may lead to a higher level of IGF-1 in brain, which could be conducive to recovery at the early stage of dMCAO.

中文翻译：

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在 dMCAO 大鼠模型中，外周循环和星形胶质细胞有助于 MSC 介导的梗塞皮层中 IGF-1 水平的增加。

背景和目的。此前，我们发现通过静脉输注同种异体间充质干/基质细胞（MSCs）可增加大脑中动脉闭塞（dMCAO）大鼠急性期梗塞皮质中胰岛素样生长因子-1（IGF-1）的水平。 ）。CD68+ 小胶质细胞和 NeuN+ 神经元是 IGF-1 来源的一部分，但不是全部。本研究旨在探索脑内源性 Iba-1+ 小胶质细胞、GFAP+ 星形胶质细胞、浸润的中性粒细胞、淋巴细胞和单核细胞/巨噬细胞以及外周循环对 MSC 输注后梗塞皮层 IGF-1 水平升高的各自贡献。材料和方法. dMCAO 在 Sprague-Dawley 大鼠中诱导缺血性脑损伤。移植组在dMCAO后1 h接受MSC输注。检查了 GFAP+ 星形胶质细胞、Iba-1+ 小胶质细胞/巨噬细胞、CD3+ 淋巴细胞、Ly6C+ 单核细胞/巨噬细胞和中性粒细胞弹性蛋白酶 (NE)+ 中性粒细胞中 IGF-1 的表达，以确定这些细胞对 IGF-1 增加的贡献。进行 ELISA 以检查缺血发作后第 2、4 和 7 天血浆中的 IGF-1 水平。结果. 总体而言，在 dMCAO 后第 2 天，在梗塞皮层、胼胝体和纹状体中，只有 5-6% 的 Iba-1+ 小胶质细胞与 IGF-1 共标记。MSC 移植不会导致更高比例的共表达 IGF-1 的 Iba-1+ 细胞。在梗塞皮层中，所有 Iba-1+/IGF-1+ 双阳性细胞也对 CD68 呈阳性。在梗塞、胼胝体和纹状体中，大多数 (50-80%) 的 GFAP+ 细胞与分支的 IGF-1 信号共同标记。MSC 处理后，GFAP+/IGF-1+ 细胞的数量进一步增加。在梗塞皮层中，大约 15% 的 IGF-1+ 细胞对 CD3 呈双阳性。MSC 治疗使浸润的 CD3+/IGF-1+ 细胞数量减少了 70%。在梗塞中，很少有 Ly6C+ 单核细胞/巨噬细胞或 NE+ 中性粒细胞表达 IGF-1，并且 MSC 处理没有诱导更高百分比的共表达 IGF-1 的这些细胞。MSC组外周血浆中IGF-1水平显着高于缺血对照组。结论。MSC 介导的梗死皮层 IGF-1 水平升高主要来自两个来源，脑中的星形胶质细胞和外周血浆。调控外周循环中的IGF-1水平可能导致脑内IGF-1水平升高，有利于dMCAO早期恢复。