Browse > Article
http://dx.doi.org/10.4062/biomolther.2013.041

A ROCK Inhibitor Blocks the Inhibitory Effect of Chondroitin Sulfate Proteoglycan on Morphological Changes of Mesenchymal Stromal/Stem Cells into Neuron-Like Cells  

Lim, Hee-Suk (Cancer Research Institute and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea)
Joe, Young Ae (Cancer Research Institute and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea)
Publication Information
Biomolecules & Therapeutics / v.21, no.6, 2013 , pp. 447-453 More about this Journal
Abstract
Chondroitin sulfate proteoglycan (CSPG) inhibits neurite outgrowth of various neuronal cell types, and CSPG-associated inhibition of neurite outgrowth is mediated by the Rho/ROCK pathway. Mesenchymal stromal/stem cells (MSCs) have the potential to differentiate into neuron-like cells under specific conditions and have been shown to differentiate into neuron-like cells by co-treatment with the ROCK inhibitor Y27632 and the hypoxia condition mimicking agent $CoCl_2$. In this study, we addressed the hypothesis that a ROCK inhibitor might be beneficial to regenerate neurons during stem cell therapy by preventing transplanted MSCs from inhibition by CSPG in damaged tissues. Indeed, dose-dependent inhibition by CSPG pretreatment was observed during morphological changes of Wharton's jelly-derived MSCs (WJ-MSCs) induced by Y27632 alone. The formation of neurite-like structures was significantly inhibited when WJ-MSCs were pre-treated with CSPG before induction under Y27632 plus $CoCl_2$ conditions, and pretreatment with a protein kinase C inhibitor reversed such inhibition. However, CSPG treatment resulted in no significant inhibition of the WJ-MSC morphological changes into neuron-like cells after initiating induction by Y27632 plus $CoCl_2$. No marked changes were detected in expression levels of neuronal markers induced by Y27632 plus $CoCl_2$ upon CSPG treatment. CSPG also blocked the morphological changes of human bone marrow-derived MSCs into neuron-like cells under other neuronal induction condition without the ROCK inhibitor, and Y27632 pre-treatment blocked the inhibitory effect of CSPG. These results suggest that a ROCK inhibitor can be efficiently used in stem cell therapy for neuronal induction by avoiding hindrance from CSPG.
Keywords
Mesenchymal stromal/stem cell; ROCK inhibitor; Chondroitin sulfate proteoglycan; PKC inhibitor; Y27632;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Can, A. and Karahuseyinoglu, S. (2007) Concise review: human umbilical cord stroma with regard to the source of fetus-derived stem cells. Stem Cells 25, 2886-2895.   DOI   ScienceOn
2 Chen, M. S., Huber, A. B., van der Haar, M. E., Frank, M., Schnell, L., Spillmann, A. A., Christ, F. and Schwab, M. E. (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434-439.   DOI   ScienceOn
3 Choi, M., Lee, H. S., Naidansaren, P., Kim, H. K., O, E., Cha, J. H., Ahn, H. Y., Yang, P. I., Shin, J. C. and Joe, Y. A. (2013) Proangiogenic features of Wharton's jelly-derived mesenchymal stromal/ stem cells and their ability to form functional vessels. Int. J. Biochem. Cell Biol. 45, 560-570.   DOI   ScienceOn
4 Datta, I., Mishra, S., Mohanty, L., Pulikkot, S. and Joshi, P. G. (2011) Neuronal plasticity of human Wharton's jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells. Cytotherapy 13, 918-932.   DOI   ScienceOn
5 Dergham, P., Ellezam, B., Essagian, C., Avedissian, H., Lubell, W. D. and McKerracher, L. (2002) Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570-6577.
6 Fu, Y. S., Cheng, Y. C., Lin, M. Y., Cheng, H., Chu, P. M., Chou, S. C., Shih, Y. H., Ko, M. H. and Sung, M. S. (2006) Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 24, 115-124.   DOI   ScienceOn
7 Gopalakrishnan, S. M., Teusch, N., Imhof, C., Bakker, M. H., Schurdak, M., Burns, D. J. and Warrior, U. (2008) Role of Rho kinase pathway in chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth in PC12 cells. J. Neurosci. Res. 86, 2214-2226.   DOI   ScienceOn
8 Kim, Y. T., Hur, E. M., Snider, W. D. and Zhou, F. Q. (2011) Role of GSK3 Signaling in Neuronal Morphogenesis. Front. Mol. Neurosci. 4, 48.
9 Krampera, M., Franchini, M., Pizzolo, G. and Aprili, G. (2007) Mesenchymal stem cells: from biology to clinical use. Blood Transfus. 5, 120-129.
10 Kubo, T., Yamaguchi, A., Iwata, N. and Yamashita, T. (2008) The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther. Clin. Risk Manag. 4, 605-615.   DOI
11 Laabs, T., Carulli, D., Geller, H. M. and Fawcett, J. W. (2005) Chondroitin sulfate proteoglycans in neural development and regeneration. Curr. Opin. Neurobiol. 15, 116-120.   DOI   ScienceOn
12 Lee, H. S., Kim, K. S., O, E. and Joe, Y. A. (2010) A Comparison of ROCK Inhibitors on Human Bone Marrow-Derived Mesenchymal Stem Cell Differentiation into Neuron-Like Cells. Biomol. Ther. 18, 386-395.   DOI   ScienceOn
13 Lehmann, M., Fournier, A., Selles-Navarro, I., Dergham, P., Sebok, A., Leclerc, N., Tigyi, G. and McKerracher, L. (1999) Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537-7547.
14 McKerracher, L., David, S., Jackson, D. L., Kottis, V., Dunn, R. J. and Braun, P. E. (1994) Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805-811.   DOI   ScienceOn
15 Lingor, P., Teusch, N., Schwarz, K., Mueller, R., Mack, H., Bahr, M. and Mueller, B. K. (2007) Inhibition of Rho kinase (ROCK) increases neurite outgrowth on chondroitin sulphate proteoglycan in vitro and axonal regeneration in the adult optic nerve in vivo. J. Neurochem. 103, 181-189.
16 Low, C. B., Liou, Y. C. and Tang, B. L. (2008) Neural differentiation and potential use of stem cells from the human umbilical cord for central nervous system transplantation therapy. J. Neurosci. Res. 86, 1670-1679.   DOI   ScienceOn
17 McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. and Chen, C. S. (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6, 483-495.   DOI   ScienceOn
18 Mitchell, K. E., Weiss, M. L., Mitchell, B. M., Martin, P., Davis, D., Morales, L., Helwig, B., Beerenstrauch, M., Abou-Easa, K., Hildreth, T., Troyer, D. and Medicetty, S. (2003) Matrix cells from Wharton's jelly form neurons and glia. Stem Cells 21, 50-60.   DOI   ScienceOn
19 Miyamoto, S., Del Re, D. P., Xiang, S. Y., Zhao, X., Florholmen, G. and Brown, J. H. (2010) Revisited and revised: is RhoA always a villain in cardiac pathophysiology? J. Cardiovasc. Transl. Res. 3, 330-343.   DOI   ScienceOn
20 Monnier, P. P., Sierra, A., Schwab, J. M., Henke-Fahle, S. and Mueller, B. K. (2003) The Rho/ROCK pathway mediates neurite growthinhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol. Cell. Neurosci. 22, 319-330.   DOI   ScienceOn
21 Mueller, B. K., Mack, H. and Teusch, N. (2005) Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discov. 4, 387-398.   DOI   ScienceOn
22 Seo, J. H. and Cho, S. R. (2012) Neurorestoration induced by mesenchymal stem cells: potential therapeutic mechanisms for clinical trials. Yonsei Med. J. 53, 1059-1067.   DOI   ScienceOn
23 Pacary, E., Legros, H., Valable, S., Duchatelle, P., Lecocq, M., Petit, E., Nicole, O. and Bernaudin, M. (2006) Synergistic effects of CoCl(2) and ROCK inhibition on mesenchymal stem cell differentiation into neuron-like cells. J. Cell Sci. 119, 2667-2678.   DOI   ScienceOn
24 Prinjha, R., Moore, S. E., Vinson, M., Blake, S., Morrow, R., Christie, G., Michalovich, D., Simmons, D. L. and Walsh, F. S. (2000) Inhibitor of neurite outgrowth in humans. Nature 403, 383-384.   DOI   ScienceOn
25 Sanchez-Ramos, J., Song, S., Cardozo-Pelaez, F., Hazzi, C., Stedeford, T., Willing, A., Freeman, T. B., Saporta, S., Janssen, W., Patel, N., Cooper, D. R. and Sanberg, P. R. (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol. 164, 247-256.   DOI   ScienceOn
26 Sivasankaran, R., Pei, J., Wang, K. C., Zhang, Y. P., Shields, C. B., Xu, X. M. and He, Z. (2004) PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat. Neurosci. 7, 261-268.   DOI   ScienceOn
27 Vinson, M., Strijbos, P. J., Rowles, A., Facci, L., Moore, S. E., Simmons, D. L. and Walsh, F. S. (2001) Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition. J. Biol. Chem. 276, 20280-20285.   DOI   ScienceOn
28 Wang, K. C., Koprivica, V., Kim, J. A., Sivasankaran, R., Guo, Y., Neve, R. L. and He, Z. (2002) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941-944.   DOI   ScienceOn
29 Winton, M. J., Dubreuil, C. I., Lasko, D., Leclerc, N. and McKerracher, L. (2002) Characterization of new cell permeable C3-like proteins that inactivate Rho and stimulate neurite outgrowth on inhibitory substrates. J. Biol. Chem. 277, 32820-32829.   DOI   ScienceOn
30 Woodbury, D., Schwarz, E. J., Prockop, D. J. and Black, I. B. (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J. Neurosci. Res. 61, 364-370.   DOI   ScienceOn