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Y. Zhang, H. Klassen, M.–T. Perez, M. Young; CNS Progenitor Cells Promote a Permissive Environment for Neurite Outgrowth via an MMP–2 Dependent Mechanism . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5751.
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© ARVO (1962-2015); The Authors (2016-present)
To examine progenitor cell–mediated alteration of inhibitory cues to neurite growth in the adult degenerating retina.
Retina progenitor cells (RPCs) were transplanted or co–transplanted with P0 neural retina to the subretinal space of rd1 mice (8–9 weeks of age). Retinas of rd1 mice were cultured or co–cultured with RPCs or with retinal explants from MMP2–/– mice. Gelatinase A (MMP–2), neurocan and CD44 expression were examined by immunocytochemistry. MMP–2 activity was detected by gelatinase zymography. Using neuronal markers, graft and host neurite extension was examined.
One month after RPCs engraftment, a large number of RPCs had migrated into the rd1 retina in association with increased retinal MMP–2 immunoreactivity and gelatinase activity as well as decreased neurocan and CD44 expression. The increased MMP–2 expression was localized in radial processes of Müller cells. MMP–2 expression was not detected in RPCs. Treatment of rd1 explants with recombinant MMP–2 or conditioned medium from rd1 retina/progenitor cell co–cultures (containing active MMP–2) led to degradation of neurocan and CD44. Co–transplantation with neural retina and RPCs resulted in a significantly increased number of neurites crossing the graft–host border. RPCs–induced enhancement of neurite outgrowth was abrogated by treatment with an MMP inhibitor or co–culturing with retinal explants from MMP2–/– mice.
The results demonstrate a new type of neurite–promoting activity associated with CNS progenitor cell transplantation and mediated by induction of MMP–2 expression in glial cells with subsequent proteolysis of the neurite outgrowth inhibitors neurocan and CD44. Progenitor cells in the retina and brain may have a novel therapeutic application in the treatment of CNS degenerative diseases.
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