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).
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 or P < 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.