Activated microglia induce bone marrow mesenchymal stem cells to produce glial cell-derived neurotrophic factor and protect neurons against oxygen-glucose deprivation injury

• Main Authors: Bingke Lv, Feng Li, Jie Fang, Limin Xu, Chengmei Sun, Jianbang Han, Tian Hua, Zhongfei Zhang, Zhiming Feng, Qinghua Wang, Xiaodan Jiang
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2016-12-01
• Series: Frontiers in Cellular Neuroscience
• Subjects: Microglia; Neuron; Tumor necrosis factor; bone marrow mesenchymal stem cell; oxygen-glucose deprivation; Glial cell-derived neurotrophic factor
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fncel.2016.00283/full

In this study, we investigated interactions among microglia (MG), bone marrow mesenchymal stem cells (BMSCs) and neurons in cerebral ischemia and the potential mechanisms using an in vitro oxygen-glucose deprivation (OGD) model. Rat BMSCs were incubated with conditioned medium (CM) from in vitro cultures of OGD-activated rat MG and murine BV2 MG cells. Effects of glial cell-derived neurotrophic factor (GDNF) on rat neuron viability, apoptosis, lactate dehydrogenase (LDH) leakage and mitochondrial membrane potential (MMP) were analyzed in this model. OGD-activated MG promoted GDNF production by BMSCs (P < 0.01). TNFα, but not IL6 or IL1β, promoted GDNF production by BMSCs (P < 0.001). GDNF or CM pre-treated BMSCs elevated neuronal viability and suppressed apoptosis (P < 0.05 or P < 0.01); these effects were inhibited by the RET antibody. GDNF activated MEK/ERK and PI3K/AKT signaling but not JNK/c-JUN. Furthermore, GDNF upregulated B cell lymphoma 2 (BCL2) and heat shock 60 kDa protein 1 (HSP60) levels, suppressed LDH leakage, and promoted MMP. Thus, activated MG produce TNFα to stimulate GDNF production by BMSCs, which prevents and repairs OGD-induced neuronal injury, possibly via regulating MEK/ERK and PI3K/AKT signaling. These findings will facilitate the prevention and treatment of neuronal injury by cerebral ischemia.