Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro.
Bone marrow-derived mesenchymal stem cells (MSCs) are of therapeutic interest in a variety of neurological diseases. In this study, we wished to determine whether human MSCs secrete factors which protect cultured rodent cortical neurons from death by trophic factor withdrawal or nitric oxide (NO) exposure. Medium conditioned by MSCs attenuated neuronal death under these conditions, a process which was dependent on intact PI(3)kinase/Akt pathway signaling. Trophic withdrawal and NO exposure in cultured cortical neurons led to reduction in Akt signaling pathways, whereas NO administration activated p38 MAPkinase in neuronal cultures. Addition of MSC-conditioned medium significantly activated the PI3kinase/Akt pathway and in neurons exposed to NO, MSC-conditioned medium reduced p38 signaling. We show that MSCs secrete brain-derived neurotrophic factor (BDNF) and addition of anti-BDNF neutralising antibodies to MSC-conditioned medium attenuated its neuroprotective effect. Exposure of neurons to BDNF increased activation of Akt pathways and protected neurons from trophic factor withdrawal. These observations determine the mechanisms of neuroprotection offered by MSC-derived factors and suggest an important role for BDNF in neuronal protection.
Department of Neurology, Institute of Clinical Neurosciences, Clinical Sciences North Bristol, University of Bristol, Bristol BS16 1LE, UK. alastair.wilkins@bristol.ac.uk
Alastair
A
Wilkins
Kevin
K
Kemp
Mark
M
Ginty
Kelly
K
Hares
Elizabeth
E
Mallam
Neil
N
Scolding
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology*; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009569:Nitric Oxide / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D017077:Culture Media, Conditioned; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases