Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Jinling Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210002, China.
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Exp Neurol. 2021 Mar;337:113542. doi: 10.1016/j.expneurol.2020.113542. Epub 2020 Dec 1.
Bone marrow mesenchymal stem cell (BMSC) transplantation is a promising treatment for ischemic stroke that carries a severe mortality and disability burden amongst the adult population globally. Thus far, BMSC transplantation has been insufficient for ameliorating neurological deficits resulting from cerebral ischemia. This shortcoming may be an outcome due to poor homing and viability of grafted cells in ischemic brain that limit the potential therapeutic benefits of BMSC transplantation. Insulin-like growth factor-1 (IGF-1), a potent anti-apoptotic agent, exerts neuroprotective effects in ischemic stroke as well as rescuing neuronal death in vitro. We hypothesized that IGF-1 could also protect BMSCs from apoptotic death, and examined whether the combination of BMSCs with IGF-1 can enhance functional recovery outcomes in mice following cerebral ischemia. Intranasal administration of BMSCs with IGF-1 was applied in a mouse focal ischemic stroke model. Our in vitro results indicated that BMSCs treated with IGF-1 exhibited less apoptotic death induced by oxygen-glucose deprivation (OGD), and an improved migratory capacity. At 14 days after ischemic insult, the combination of BMSCs with IGF-1 resulted in a larger number of NeuN/BrdU and Glut-1/BrdU co-labeled cells in the areas contiguous to the ischemic core than IGF-1 or BMSC treatment alone. Western blot assays demonstrated that the protein levels of BDNF, VEGF and Ang-1 were significantly upregulated in the peri-infarct region in the combination treatment group compared with single IGF- 1 or BMSC treatment. Co-administration of BMSCs and IGF-1 markedly increases local cerebral blood flow and promoted better functional behavior outcomes. These data suggest that intranasal delivery of BMSCs in conjunction with IGF-1 strengthened functional recovery following ischemia via increasing neurogenesis and angiogenesis, providing a novel optimized strategy for improving the therapeutic efficacy of BMSC transplantation for ischemia.
骨髓间充质干细胞（BMSC）移植是一种有前途的治疗缺血性中风的方法，在全球范围内，这种方法给成年人口带来了严重的死亡率和残疾负担。到目前为止，BMSC 移植对于改善脑缺血引起的神经功能缺损还远远不够。这种缺陷可能是由于移植细胞在缺血性大脑中的归巢和活力差，限制了 BMSC 移植的潜在治疗益处所致。胰岛素样生长因子-1（IGF-1）是一种有效的抗凋亡剂，在缺血性中风中具有神经保护作用，并能挽救体外神经元死亡。我们假设 IGF-1 也可以保护 BMSC 免受凋亡死亡，并研究了 BMSC 与 IGF-1 的联合应用是否可以增强缺血后小鼠的功能恢复。我们在小鼠局灶性缺血性中风模型中应用了 BMSC 与 IGF-1 的联合鼻内给药。我们的体外结果表明，IGF-1 处理的 BMSC 在氧葡萄糖剥夺（OGD）诱导的凋亡死亡减少，迁移能力提高。在缺血损伤后 14 天，与 IGF-1 或 BMSC 单一治疗相比，BMSC 与 IGF-1 的联合治疗导致与缺血核心相邻区域的 NeuN/BrdU 和 Glut-1/BrdU 共标记细胞数量更多。Western blot 检测表明，与 IGF-1 或 BMSC 单一治疗相比，联合治疗组在梗死周边区 BDNF、VEGF 和 Ang-1 的蛋白水平显著上调。BMSCs 和 IGF-1 的共同给药显著增加了局部脑血流量，并促进了更好的功能行为结果。这些数据表明，BMSC 与 IGF-1 的联合鼻内给药通过增加神经发生和血管生成，增强了缺血后的功能恢复，为改善 BMSC 移植治疗缺血的疗效提供了一种新的优化策略。
