title: Activated Microglia Induce Bone Marrow Mesenchymal Stem Cells to Produce Glial Cell-Derived Neurotrophic Factor and Protect Neurons Against Oxygen-Glucose Deprivation Injury.
abstract: 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 anin vitrooxygen-glucose deprivation (OGD) model. Rat BMSCs were incubated with conditioned medium (CM) fromin vitrocultures 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). Tumor necrosis factor-α (TNFα), but not interleukin-6 (IL6) or interleukin 1β (IL1β), promoted GDNF production by BMSCs (P< 0.001). GDNF or CM pre-treated BMSCs elevated neuronal viability and suppressed apoptosis (P< 0.05 orP< 0.01); these effects were inhibited by the RET antibody. GDNF activated MEK/ERK and phosphoinositide-3-kinase (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.
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Bingke
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Chengmei
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Jianbang
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Hua
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Zhongfei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 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 Guangzhou, China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Jiang
keywords: bone marrow mesenchymal stem cell; glial cell-derived neurotrophic factor; microglia; neuron; oxygen-glucose deprivation; tumor necrosis factor