Mesenchymal stem cells support dorsal root ganglion neurons survival by inhibiting the metalloproteinase pathway.
The positive effect of adult undifferentiated mesenchymal stem cells (MSCs) on neuronal survival has already been reported, although the mechanisms by which MSCs exert their effect are still a matter of debate. Here we have demonstrated that MSCs are able to prolong the survival of dorsal root ganglion (DRG) neurons mainly by inhibiting some proteolytic enzymes, and in particular the pathway of metalloproteinases (MMPs), a family of proteins that are involved in many neuronal processes, including survival. The inhibition of MMPs was both direct, by acting on MT-MMP1, and indirect, by acting on those proteins that regulate MMPs' activation, such as Timp-1 and Sparc. The importance of the MMPs' down-regulation for neuronal survival was also demonstrated by using N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycyl hydroxamic acid (NNGH), a wide range inhibitor of metalloproteinases, which was able to increase the survival of DRG neurons in a significant manner. The down-regulation of MMPs, obtained both by MSC contact and by chemical inhibition, led to the inactivation of caspase 3, the executor of apoptotic death in DRG neurons cultured alone, while caspase 7 was found to be irrelevant for the apoptotic process. The capacity of MSCs to prevent apoptosis mainly by inactivating the metalloproteinase pathway is an important finding that sheds light on MSCs' mechanism of action, making undifferentiated MSCs a promising tool for the treatment of many different neurodegenerative pathologies.
Dipartimento di Neuroscienze e Tecnologie Biomediche, Università degli Studi di Milano-Bicocca, via Cadore 48, 20052 Monza, Italy. arianna.scuteri@unimib.it
A
A
Scuteri
M
M
Ravasi
S
S
Pasini
M
M
Bossi
G
G
Tredici
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D006877:Hydroxamic Acids; C500716:N-isobutyl-N-(4-methoxyphenylsulfonyl)glycylhydroxamic acid; D011480:Protease Inhibitors; D013449:Sulfonamides; D045726:Metalloproteases