Mesenchymal stem cell-secreted superoxide dismutase promotes cerebellar neuronal survival.
It has been postulated that bone marrow-derived mesenchymal stem cells (MSCs) might be effective treatments for neurodegenerative disorders either by replacement of lost cells by differentiation into functional neural tissue; modulation of the immune system to prevent further neurodegeneration; and/or provision of trophic support for the diseased nervous system. Here we have performed a series of experiments showing that human bone marrow-derived MSCs are able to protect cultured rodent cerebellar neurons, and specifically cells expressing Purkinje cell markers, against either nitric oxide exposure or withdrawal of trophic support via cell-cell contact and/or secretion of soluble factors, or through secretion of soluble factors alone. We have demonstrated that MSCs protect cerebellar neurons against toxic insults via modulation of both the phosphatidylinositol 3-kinase/Akt and MAPK pathways and defined superoxide dismutase 3 as a secreted active antioxidant biomolecule by which MSCs modulate, at least in part, their neuroprotective effect on cerebellar cells in vitro. Together, the results demonstrate new and specific mechanisms by which MSCs promote cerebellar neuronal survival and add further evidence to the concept that MSCs may be potential therapeutic agents for neurological disorders involving the cerebellum.
Kemp
Kevin
K
Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, Clinical Sciences North Bristol, University of Bristol, Bristol, UK. kevin.kemp@bristol.ac.uk
Hares
Kelly
K
Mallam
Elizabeth
E
Heesom
Kate J
KJ
Scolding
Neil
N
Wilkins
Alastair
A
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002450:Cell Communication; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D017077:Culture Media, Conditioned; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D009569:Nitric Oxide / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017077:Culture Media, Conditioned; D009569:Nitric Oxide; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases