Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid

Journal of Lipid Research

Volumn 54, Issue 5, 2013, Pages 1192-1206

  Frisca, Frisca ^a   Crombie, Duncan E ^a,b   Dottori, Mirella ^a   Goldshmit, Yona ^c   Pébay, Alice ^a,b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b ROYAL VICTORIAN EYE AND EAR HOSPITAL   (Australia)

^c MONASH UNIVERSITY   (Australia)

Author keywords

Human embryonic stem cell; Induced pluripotent stem cell; Rho pathway

Indexed keywords

AUTOTAXIN; LYSOPHOSPHATIDIC ACID; LYSOPHOSPHATIDIC ACID 1; LYSOPHOSPHATIDIC ACID 2; LYSOPHOSPHATIDIC ACID 3; LYSOPHOSPHATIDIC ACID 4; LYSOPHOSPHATIDIC ACID 5; LYSOPHOSPHATIDIC ACID RECEPTOR; MESSENGER RNA; MYOSIN LIGHT CHAIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RHO KINASE; UNCLASSIFIED DRUG;

ACTIN FILAMENT; APOPTOSIS; ARTICLE; CELL EXPANSION; CELL PROLIFERATION; CELL STRUCTURE; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; DISEASE ASSOCIATION; DOWN REGULATION; EMBRYO; EMBRYONIC STEM CELL; ENZYME ACTIVATION; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE SILENCING; HUMAN; HUMAN CELL; IN VITRO STUDY; INTRACELLULAR SIGNALING; MOLECULAR DYNAMICS; NERVE CELL CHARACTERISTICS AND FUNCTIONS; NERVE CELL DIFFERENTIATION; NERVOUS SYSTEM DEVELOPMENT; NERVOUS SYSTEM INFLAMMATION; NEURAL STEM CELL; NEUROSPHERE FORMATION; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION;

CELL DIFFERENTIATION; HUMANS; INDUCED PLURIPOTENT STEM CELLS; LYSOPHOSPHOLIPIDS; MYOSIN LIGHT CHAINS; NEURAL STEM CELLS; NEURONS; PHOSPHORYLATION; RECEPTORS, LYSOPHOSPHATIDIC ACID; RHO GTP-BINDING PROTEINS; RHO-ASSOCIATED KINASES; SIGNAL TRANSDUCTION;

EID: 84876800996     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M032284     Document Type: Article

References (81)

1. Frisca F., R. A. Sabbadini, Y. Goldshmit, and A. Pébay. 2012. Biological effects of lysophosphatidic acid in the nervous system. Int. Rev. Cell Mol. Biol. 296 : 273-322.
2. Pasternack, S. M., I. von Kugelgen, K. A. Aboud, Y. A. Lee, F. Ruschendorf, K. Voss, A. M. Hillmer, G. J. Molderings, T. Franz, A. Ramirez, et al. 2008. G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat. Genet. 40 : 329-334.
3. Tabata, K., K. Baba, A. Shiraishi, M. Ito, and N. Fujita. 2007. The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 363 : 861-866.
4. Murakami, M., A. Shiraishi, K. Tabata, and N. Fujita. 2008. Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1- phosphate and lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 371 : 707-712.
5. Nieto-Posadas, A., G. Picazo-Juarez, I. Llorente, A. Jara-Oseguera, S. Morales-Lazaro, D. Escalante-Alcalde, L. D. Islas, and T. Rosenbaum. 2012. Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. Nat. Chem. Biol. 8 : 78-85.
6. McIntyre, T. M., A. V. Pontsler, A. R. Silva, A. St Hilaire, Y. Xu, J. C. Hinshaw, G. A. Zimmerman, K. Hama, J. Aoki, H. Arai, et al. 2003. Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist. Proc. Natl. Acad. Sci. USA. 100 : 131-136.
7. Pébay, A., C. S. Bonder, and S. M. Pitson. 2007. Stem cell regulation by lysophospholipids. Prostaglandins Other Lipid Mediat. 84 : 83-97.
8. Pitson, S. M., and A. Pebay. 2009. Regulation of stem cell pluripotency and neural differentiation by lysophospholipids. Neurosignals. 17 : 242-254.
9. Yamanaka, S. 2012. Induced pluripotent stem cells: Past, present, and future. Cell Stem Cell. 10 : 678-684.
10. Pera, M. F., J. Andrade, S. Houssami, B. Reubinoff, A. Trounson, E. G. Stanley, D. W. Oostwaard, and C. Mummery. 2004. Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J. Cell Sci. 117 : 1269-1280.
11. Dottori, M., A. Pebay, and M. F. Pera. 2010. Neural differentiation of human embryonic stem cells. In Neural Stem Cells: Methods and Protocols. 2 nd edition. L. P. Weiner, editor. Humana Press. 19-30.
12. Denham, M., and M. Dottori. 2009. Signals involved in neural differentiation of human embryonic stem cells. Neurosignals. 17 : 234-241.
13. Cui, H. L., and J. T. Qiao. 2006. Promotive action of lysophosphatidic acid on proliferation of rat embryonic neural stem cells and their differentiation to cholinergic neurons in vitro. Sheng Li Xue Bao. 58 : 547-555.
14. Svetlov, S. I., T. N. Ignatova, K. K. Wang, R. L. Hayes, D. English, and V. G. Kukekov. 2004. Lysophosphatidic acid induces clonal generation of mouse neurospheres via proliferation of Sca-1-and AC133-positive neural progenitors. Stem Cells Dev. 13 : 685-693.
15. Harada, J., M. Foley, M. A. Moskowitz, and C. Waeber. 2004. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J. Neurochem. 88 : 1026-1039.
16. Sun, Y., J-S. Nam, D-H. Han, N-H. Kim, H-K. Choi, J. K. Lee, H. J. Rhee, and S-O. Huh. 2010. Lysophosphatidic acid induces upregulation of Mcl-1 and protects apoptosis in a PTX-dependent manner in H19-7 cells. Cell. Signal. 22 : 484-494.
17. Fukushima, N., S. Shano, R. Moriyama, and J. Chun. 2007. Lysophosphatidic acid stimulates neuronal differentiation of cortical neuroblasts through the LPA1-G(i/o) pathway. Neurochem. Int. 50 : 302-307.
18. Rhee, H. J., J-S. Nam, Y. Sun, M-J. Kim, H-K. Choi, D-H. Han, N-H. Kim, and S-O. Huh. 2006. Lysophosphatidic acid stimulates cAMP accumulation and cAMP response element-binding protein phosphorylation in immortalized hippocampal progenitor cells. Neuroreport. 17 : 523-526.
19. Yung, Y. C., T. Mutoh, M-E. Lin, K. Noguchi, R. R. Rivera, J. W. Choi, M. A. Kingsbury, and J. Chun. 2011. Lysophosphatidic acid signaling may initiate fetal hydrocephalus. Sci. Transl. Med. 3 : 99ra87.
20. Saito, S. 1997. Effects of lysophosphatidic acid on primary cultured chick neurons. Neurosci. Lett. 229 : 73-76.
21. Fukushima, N., I. Ishii, Y. Habara, C. B. Allen, and J. Chun. 2002. Dual regulation of actin rearrangement through lysophosphatidic acid receptor in neuroblast cell lines: Actin depolymerization by Ca(2+)-alpha-actinin and polymerization by rho. Mol. Biol. Cell. 13 : 2692-2705.
22. Fukushima, N., J. A. Weiner, D. Kaushal, J. J. A. Contos, S. K. Rehen, M. A. Kingsbury, K. Y. Kim, and J. Chun. 2002. Lysophosphatidic acid influences the morphology and motility of young, postmitotic cortical neurons. Mol. Cell. Neurosci. 20 : 271-282.
23. Sayas, C. L., A. Ariaens, B. Ponsioen, and W. H. Moolenaar. 2006. GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. Mol. Biol. Cell. 17 : 1834-1844.
24. Sayas, C. L., M. T. Moreno-Flores, J. Avila, and F. Wandosell. 1999. The neurite retraction induced by lysophosphatidic acid increases Alzheimer's disease-like Tau phosphorylation. J. Biol. Chem. 274 : 37046-37052.
25. Pai, K. S., and D. D. Cunningham. 2002. Geldanamycin specifically modulates thrombin-mediated morphological changes in mouse neuroblasts. J. Neurochem. 80 : 715-718.
26. Jalink, K., E. J. van Corven, T. Hengeveld, N. Morii, S. Narumiya, and W. H. Moolenaar. 1994. Inhibition of lysophosphatidate-and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J. Cell Biol. 126 : 801-810.
27. Kozma, R., S. Sarner, S. Ahmed, and L. Lim. 1997. Rho family GTPases and neuronal growth cone remodelling: Relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol. Cell. Biol. 17 : 1201-1211.
28. Fukushima, N., Y. Kimura, and J. Chun. 1998. A single receptor encoded by vzg-1/lpA1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid. Proc. Natl. Acad. Sci. USA. 95 : 6151-6156.
29. Kranenburg, O., M. Poland, M. Gebbink, L. Oomen, and W. H. Moolenaar. 1997. Dissociation of LPA-induced cytoskeletal contraction from stress fi ber formation by differential localization of RhoA. J. Cell Sci. 110 : 2417-2427.
30. Kranenburg, O., M. Poland, F. P. van Horck, D. Drechsel, A. Hall, and W. H. Moolenaar. 1999. Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: Induction of neurite retraction. Mol. Biol. Cell. 10 : 1851-1857.
31. Smalheiser, N. R., and J. Y. Ali. 1994. Acute neurite retraction triggered by lysophosphatidic acid: Timing of the inhibitory effects of genistein. Brain Res. 660 : 309-318.
32. Fukushima, N., D. Furuta, and T. Tsujiuchi. 2011. Coordinated interactions between actin and microtubules through crosslinkers in neurite retraction induced by lysophosphatidic acid. Neurochem. Int. 59 : 109-113.
33. Kimura, Y., A. Schmitt, N. Fukushima, I. Ishii, H. Kimura, A. R. Nebreda, and J. Chun. 2001. Two novel Xenopus homologs of mammalian LP(A1)/EDG-2 function as lysophosphatidic acid receptors in Xenopus oocytes and mammalian cells. J. Biol. Chem. 276 : 15208-15215.
34. Ishii, I., J. J. Contos, N. Fukushima, and J. Chun. 2000. Functional comparisons of the lysophosphatidic acid receptors, LP(A1)/VZG-1/EDG-2, LP(A2)/EDG-4, and LP(A3)/EDG-7 in neuronal cell lines using a retrovirus expression system. Mol. Pharmacol. 58 : 895-902.
35. Contos, J. J. A., N. Fukushima, J. A. Weiner, D. Kaushal, and J. Chun. 2000. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc. Natl. Acad. Sci. USA. 97 : 13384-13389.
36. Fukushima, N., J. A. Weiner, and J. Chun. 2000. Lysophosphatidic acid (LPA) is a novel extracellular regulator of cortical neuroblast morphology. Dev. Biol. 228 : 6-18.
37. Hecht, J. H., J. A. Weiner, S. R. Post, and J. Chun. 1996. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell Biol. 135 : 1071-1083.
38. Kingsbury, M. A., S. K. Rehen, J. J. A. Contos, C. M. Higgins, and J. Chun. 2003. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat. Neurosci. 6 : 1292-1299.
39. Dottori, M., J. Leung, A. M. Turnley, and A. Pebay. 2008. Lysophosphatidic acid inhibits neuronal differentiation of neural stem/progenitor cells derived from human embryonic stem cells. Stem Cells. 26 : 1146-1154.
40. Shin, S., M. Mitalipova, S. Noggle, D. Tibbitts, A. Venable, R. Rao, and S. L. Stice. 2006. Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defi ned adherent culture conditions. Stem Cells. 24 : 125-138.
41. Hurst, J. H., J. Mumaw, D. W. Machacek, C. Sturkie, P. Callihan, S. L. Stice, and S. B. Hooks. 2008. Human neural progenitors express functional lysophospholipid receptors that regulate cell growth and morphology. BMC Neurosci. 9 : 118.
42. Yu, J., M. A. Vodyanik, K. Smuga-Otto, J. Antosiewicz-Bourget, J. L. Frane, S. Tian, J. Nie, G. A. Jonsdottir, V. Ruotti, R. Stewart, et al. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science. 318: 1917-1920.
43. Reubinoff, B. E., M. F. Pera, C. Y. Fong, A. Trounson, and A. Bongso. 2000. Embryonic stem cell lines from human blastocysts: Somatic differentiation in vitro. Nat. Biotechnol. 18 : 399-404.
44. Liu, J., P. J. Verma, M. V. Evans-Galea, M. B. Delatycki, A. Michalska, J. Leung, D. Crombie, J. P. Sarsero, R. Williamson, M. Dottori, et al. 2011. Generation of induced pluripotent stem cell lines from Friedreich ataxia patients. Stem Cell Rev. 7 : 703-713.
45. Reubinoff, B. E., P. Itsykson, T. Turetsky, M. F. Pera, E. Reinhartz, A. Itzik, and T. Ben-Hur. 2001. Neural progenitors from human embryonic stem cells. Nat. Biotechnol. 19 : 1134-1140.
46. Song, B., G. Sun, D. Herszfeld, A. Sylvain, N. V. Campanale, C. E. Hirst, S. Caine, H. C. Parkington, M. A. Tonta, H. A. Coleman, et al. 2012. Neural differentiation of patient specific iPS cells as a novel approach to study the pathophysiology of multiple sclerosis. Stem Cell Res. 8 : 259-273.
47. Chen, G., Z. Hou, D. R. Gulbranson, and J. A. Thomson. 2010. Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells. Cell Stem Cell. 7 : 240-248.
48. Ohta, H., K. Sato, N. Murata, A. Damirin, E. Malchinkhuu, J. Kon, T. Kimura, M. Tobo, Y. Yamazaki, T. Watanabe, et al. 2003. Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol. Pharmacol. 64 : 994-1005.
49. Leesnitzer, L. M., D. J. Parks, R. K. Bledsoe, J. E. Cobb, J. L. Collins, T. G. Consler, R. G. Davis, E. A. Hull-Ryde, J. M. Lenhard, L. Patel, et al. 2002. Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry. 41 : 6640-6650.
50. Vogelsgesang, M., A. Pautsch, and K. Aktories. 2007. C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins. Naunyn Schmiedebergs Arch. Pharmacol. 374 : 347-360.
51. Ishizaki, T., M. Uehata, I. Tamechika, J. Keel, K. Nonomura, M. Maekawa, and S. Narumiya. 2000. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol. Pharmacol. 57 : 976-983.
52. Luo, L. 2002. Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu. Rev. Cell Dev. Biol. 18 : 601-635.
53. Bilic, J., and J. C. I. Belmonte. 2012. Concise review: Induced pluripotent stem cells versus embryonic stem cells: Close enough or yet too far apart? Stem Cells. 30 : 33-41.
54. Pébay, A., R. C. Wong, S. M. Pitson, E. J. Wolvetang, G. S. Peh, A. Filipczyk, K. L. Koh, I. Tellis, L. T. Nguyen, and M. F. Pera. 2005. Essential roles of sphingosine-1-phosphate and platelet-derived growth factor in the maintenance of human embryonic stem cells. Stem Cells. 23 : 1541-1548.
55. Bächner, D., M. Ahrens, N. Betat, D. Schröder, and G. Gross. 1999. Developmental expression analysis of murine autotaxin (ATX). Mech. Dev. 84 : 121-125.
56. Dorsam, R. T., and J. S. Gutkind. 2007. G-protein-coupled receptors and cancer. Nat. Rev. Cancer. 7 : 79-94.
57. Holtsberg, F. W., M. R. Steiner, J. N. Keller, R. J. Mark, M. P. Mattson, and S. M. Steiner. 1998. Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons. J. Neurochem. 70 : 66-76.
58. Cui, H-L., and J. Qiao. 2007. Effect of lysophosphatidic acid on differentiation of embryonic neural stem cells into neuroglial cells in rats in vitro. Sheng Li Xue Bao (Acta Physiologica Sinica). 59 : 759-764.
59. Cui, H.-L., and J.-T. Qiao. 2006. Promotive action of lysophosphatidic acid on proliferation of rat embryonic neural stem cells and their differentiation to cholinergic neurons in vitro. Sheng Li Xue Bao (Acta Physiologica Sinica). 58: 547-555.
60. Spohr, T. C., J. W. Choi, S. E. Gardell, D. R. Herr, S. K. Rehen, F. C. A. Gomes, and J. Chun. 2008. Lysophosphatidic acid receptor-dependent secondary effects via astrocytes promote neuronal differentiation. J. Biol. Chem. 283 : 7470-7479.
61. Tigyi, G., D. J. Fischer, A. Sebok, C. Yang, D. L. Dyer, and R. Miledi. 1996. Lysophosphatidic acid-induced neurite retraction in PC12 cells: Control by phosphoinositide-Ca2+ signaling and Rho. J. Neurochem. 66 : 537-548.
62. Watanabe, K., M. Ueno, D. Kamiya, A. Nishiyama, M. Matsumura, T. Wataya, J. B. Takahashi, S. Nishikawa, K. Muguruma, and Y. Sasai. 2007. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol. 25 : 681-686.
63. Damoiseaux, R., S. P. Sherman, J. A. Alva, C. Peterson, and A. D. Pyle. 2009. Integrated chemical genomics reveals modifi ers of survival in human embryonic stem cells. Stem Cells. 27: 533-542.
64. Koyanagi, M., J. Takahashi, Y. Arakawa, D. Doi, H. Fukuda, H. Hayashi, S. Narumiya, and N. Hashimoto. 2008. Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell-derived neural precursors. J. Neurosci. Res. 86 : 270-280.
65. Harb, N., T. K. Archer, and N. Sato. 2008. The Rho-Rock-Myosin signaling axis determines cell-cell integrity of self-renewing pluripotent stem cells. PLoS ONE. 3 : E3001.
66. Mills, J. C., N. L. Stone, J. Erhardt, and R. N. Pittman. 1998. Apoptotic membrane blebbing is regulated by myosin light chain phosphorylation. J. Cell Biol. 140 : 627-636.
67. Dubreuil, C. I., M. J. Winton, and L. McKerracher. 2003. Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J. Cell Biol. 162 : 233-243.
68. Krawetz, R. J., X. Li, and D. E. Rancourt. 2009. Human embryonic stem cells: Caught between a ROCK inhibitor and a hard place. Bioessays. 31 : 336-343.
69. Ikeda, H., K. Nagashima, M. Yanase, T. Tomiya, M. Arai, Y. Inoue, K. Tejima, T. Nishikawa, M. Omata, S. Kimura, et al. 2003. Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 285 : G880-G886.
70. Lai J. M., C. Y. Lu, H. F. Yang-Yen, and Z. F. Chang. 2001. Lysophosphatidic acid promotes phorbol-ester-induced apoptosis in TF-1 cells by interfering with adhesion. Biochem. J. 359 : 227-233.
71. Picard-Riera, N., B. Nait-Oumesmar, and A. Baron-Van Evercooren. 2004. Endogenous adult neural stem cells: Limits and potential to repair the injured central nervous system. J. Neurosci. Res. 76 : 223-231.
72. Jin, K., X. Wang, L. Xie, X. O. Mao, and D. A. Greenberg. 2010. Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice. Proc. Natl. Acad. Sci. USA. 107 : 7993-7998.
73. Nakayama, D., T. Matsuyama, H. Ishibashi-Ueda, T. Nakagomi, Y. Kasahara, H. Hirose, A. Kikuchi-Taura, D. M. Stern, H. Mori, and A. Taguchi. 2010. Injury-induced neural stem/progenitor cells in post-stroke human cerebral cortex. Eur. J. Neurosci. 31 : 90-98.
74. Richardson, R. M., A. Singh, D. Sun, H. L. Fillmore, D. W. Dietrich 3rd, and M. R. Bullock. 2010. Stem cell biology in traumatic brain injury: Effects of injury and strategies for repair. J. Neurosurg. 112 : 1125-1138.
75. Fukushima, N. 2004. LPA in neural cell development. J. Cell. Biochem. 92 : 993-1003.
76. Steiner, M. R., J. R. Urso, J. Klein, and S. M. Steiner. 2002. Multiple astrocyte responses to lysophosphatidic acids. Biochim. Biophys. Acta. 1582 : 154-160.
77. Eichholtz, T., K. Jalink, I. Fahrenfort, and W. H. Moolenaar. 1993. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem. J. 291 : 677-680.
78. Tigyi, G., L. Hong, M. Yakubu, H. Parfenova, M. Shibata, and C. W. Leffler. 1995. Lysophosphatidic acid alters cerebrovascular reactivity in piglets. Am. J. Physiol. 268 : H2048-H2055.
79. Savaskan, N. E., L. Rocha, M. R. Kotter, A. Baer, G. Lubec, L. A. van Meeteren, Y. Kishi, J. Aoki, W. H. Moolenaar, R. Nitsch, et al. 2007. Autotaxin (NPP-2) in the brain: Cell type-specific expression and regulation during development and after neurotrauma. Cell. Mol. Life Sci. 64 : 230-243.
80. Goldshmit, Y., R. Matteo, T. Sztal, F. Ellett, F. Frisca, K. Moreno, D. Crombie, G. J. Lieschke, P. D. Currie, R. A. Sabbadini, et al. 2012. Blockage of lysophosphatidic acid signaling improves spinal cord injury outcomes. Am. J. Pathol. 181 : 978-992.
81. Kimura, A., T. Ohmori, Y. Kashiwakura, R. Ohkawa, S. Madoiwa, J. Mimuro, K. Shimazaki, Y. Hoshino, Y. Yatomi, and Y. Sakata. 2008. Antagonism of sphingosine 1-phosphate receptor-2 enhances migration of neural progenitor cells toward an area of brain. Stroke. 39 : 3411-3417.