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The Journal of Neuroscience, April 25, 2007, 27(17):4499-4506; doi:10.1523/JNEUROSCI.0200-07.2007

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Development/Plasticity/Repair
CNS Progenitor Cells Promote a Permissive Environment for Neurite Outgrowth via a Matrix Metalloproteinase-2-Dependent Mechanism

Yiqin Zhang,¹ Henry J. Klassen,²  Budd A. Tucker,¹ Maria-Thereza R. Perez,³ and Michael J. Young¹

¹Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, ²Stem Cell Research, Children's Hospital of Orange Country, Orange, California 92868, and ³Wallenberg Retina Center, Department of Ophthalmology, Lund University, SE-22100 Lund, Sweden

Correspondence should be addressed to Michael J. Young, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114. Email: mikey{at}vision.eri.harvard.edu

Transplantation of progenitor cells to the CNS has shown promise in neuronal and glial replacement and as a means of rescuing host neurons from apoptosis. Here we examined the effect of progenitor grafts on neurite extension in the degenerating retina of rd1 (retinal degeneration 1) mice. Transplantation of retinal progenitor cells induced increased matrix metalloproteinase-2 (MMP2) secretion, partly from activated glial cells, which was then activated by neuronally expressed MMP14. Active MMP2 resulted in proteolysis of the neurite outgrowth inhibitors CD44 and neurocan in the degenerative retina, allowing significantly increased neurite outgrowth across the border between abutting nondystrophic and rd1 retinas. Progenitor-induced enhancement of outgrowth was abrogated by an MMP inhibitor or by coculture with retinal explants from MMP2^–/– mice. This study provides the first identification of an MMP2-dependent mechanism by which exogenous progenitor cells alter the host environment to promote neural regeneration. This suggests a novel therapeutic role for progenitor cells in the treatment of CNS degenerative diseases.

Key words: retina; progenitor cell; cell transplantation; cell migration; neurite outgrowth; MMP-2

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Received Jan. 17, 2006; accepted Feb. 10, 2007.

Correspondence should be addressed to Michael J. Young, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114. Email: mikey{at}vision.eri.harvard.edu

This article has been cited by other articles:

				J. Sancho-Pelluz, K. A. Wunderlich, U. Rauch, F. J. Romero, T. van Veen, G. A. Limb, P. R. Crocker, and M.-T. Perez Sialoadhesin Expression in Intact Degenerating Retinas and Following Transplantation Invest. Ophthalmol. Vis. Sci., December 1, 2008; 49(12): 5602 - 5610. [Abstract] [Full Text] [PDF]

				P. Charalambous, L. A. Hurst, and S. Thanos Engrafted Chicken Neural Tube-Derived Stem Cells Support the Innate Propensity for Axonal Regeneration within the Rat Optic Nerve Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3513 - 3524. [Abstract] [Full Text] [PDF]

				T. V. Johnson and K. R. Martin Development and Characterization of an Adult Retinal Explant Organotypic Tissue Culture System as an In Vitro Intraocular Stem Cell Transplantation Model Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3503 - 3512. [Abstract] [Full Text] [PDF]

				B. Tucker, H. Klassen, L. Yang, D. F. Chen, and M. J. Young Elevated MMP Expression in the MRL Mouse Retina Creates a Permissive Environment for Retinal Regeneration Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1686 - 1695. [Abstract] [Full Text] [PDF]

				O. Einstein and T. Ben-Hur The Changing Face of Neural Stem Cell Therapy in Neurologic Diseases Arch Neurol, April 1, 2008; 65(4): 452 - 456. [Abstract] [Full Text] [PDF]

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