Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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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)
  • Received : 2013.05.13
  • Accepted : 2013.05.30
  • Published : 2013.11.30
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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.

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References

  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. https://doi.org/10.1634/stemcells.2007-0417
  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. https://doi.org/10.1038/35000219
  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. https://doi.org/10.1016/j.biocel.2012.12.001
  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. https://doi.org/10.3109/14653249.2011.579957
  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. https://doi.org/10.1634/stemcells.2005-0053
  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. https://doi.org/10.1002/jnr.21671
  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. https://doi.org/10.2147/TCRM.S2907
  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. https://doi.org/10.1016/j.conb.2005.01.014
  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. https://doi.org/10.4062/biomolther.2010.18.4.386
  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. 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.
  15. 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. https://doi.org/10.1002/jnr.21624
  16. 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. https://doi.org/10.1016/S1534-5807(04)00075-9
  17. 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. https://doi.org/10.1016/0896-6273(94)90247-X
  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. https://doi.org/10.1634/stemcells.21-1-50
  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. https://doi.org/10.1007/s12265-010-9192-8
  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. https://doi.org/10.1016/S1044-7431(02)00035-0
  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. https://doi.org/10.1038/nrd1719
  22. 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. https://doi.org/10.1242/jcs.03004
  23. 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. https://doi.org/10.1038/35000287
  24. 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. https://doi.org/10.1006/exnr.2000.7389
  25. 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. https://doi.org/10.3349/ymj.2012.53.6.1059
  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. https://doi.org/10.1038/nn1193
  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. https://doi.org/10.1074/jbc.M100345200
  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. https://doi.org/10.1038/nature00867
  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. https://doi.org/10.1074/jbc.M201195200
  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. https://doi.org/10.1002/1097-4547(20000815)61:4<364::AID-JNR2>3.0.CO;2-C

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