Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Stem Cells Dev. 2020 Jun 1;29(11):714-727. doi: 10.1089/scd.2019.0235. Epub 2020 Apr 21.
Neuroinflammation is associated with the pathogenesis of all types of neurological disease, in which microglial cells play a critical role. In response to disturbances in the microenvironment, microglia (MG) become activated and differentiate into either an M1 phenotype, which has a proinflammatory damaging effect, or an M2 phenotype, which plays an anti-inflammatory and reparative role. Thus, modulating microglial polarization is a suitable strategy to treat neuroinflammatory disorders. Glial cell-derived neurotrophic factor (GDNF) is a neurotrophic mediator that exerts neuroprotective effects during neurological diseases. In this study, we predicted that adipose-derived stem cells (ADSCs) could produce GDNF and investigated the effects of GDNF on microglial M1/M2 polarization. Furthermore, we determined whether GDNF modulates microglial activation and polarization via the phosphoinositide-3-kinase (PI3K)/AKT signaling pathway. We found that the secretion of inflammatory cytokines in lipopolysaccharide-stimulated MG was downregulated, whereas the anti-inflammatory mediators in interleukin-4-stimulated MG were upregulated obviously, following pretreatment with ADSCs or GDNF. In addition, GDNF produced by ADSCs inhibited the MG M1 phenotype and promoted the M2 phenotype by upregulating the PI3K/ATK pathway. These results reveal that GDNF produced by ADSCs might be useful for the regulation of neuroinflammatory disorders.
神经炎症与所有类型的神经疾病的发病机制有关，其中小胶质细胞起着关键作用。小胶质细胞（MG）在微环境紊乱时被激活并分化为 M1 表型，具有促炎损伤作用，或 M2 表型，发挥抗炎和修复作用。因此，调节小胶质细胞极化是治疗神经炎症疾病的一种合适策略。胶质细胞源性神经营养因子（GDNF）是一种神经营养介质，在神经疾病中发挥神经保护作用。在本研究中，我们预测脂肪来源干细胞（ADSCs）可以产生 GDNF，并研究 GDNF 对小胶质细胞 M1/M2 极化的影响。此外，我们还确定了 GDNF 是否通过磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）信号通路调节小胶质细胞的激活和极化。我们发现，ADSCs 或 GDNF 预处理可下调脂多糖刺激的 MG 中炎症细胞因子的分泌，而上调白细胞介素 4 刺激的 MG 中抗炎介质的表达。此外，ADSCs 产生的 GDNF 通过上调 PI3K/AKT 通路抑制 MG M1 表型并促进 M2 表型。这些结果表明，ADSCs 产生的 GDNF 可能有助于调节神经炎症疾病。
