title: Simulated microgravity facilitates cell migration and neuroprotection after bone marrow stromal cell transplantation in spinal cord injury.
abstract: BACKGROUND
  Recently, cell-based therapy has gained significant attention for the treatment of central nervous system diseases. Although bone marrow stromal cells (BMSCs) are considered to have good engraftment potential, challenges due to in vitro culturing, such as a decline in their functional potency, have been reported. Here, we investigated the efficacy of rat BMSCs (rBMSCs) cultured under simulated microgravity conditions, for transplantation into a rat model of spinal cord injury (SCI).
  
  
  METHODS
  rBMSCs were cultured under two different conditions: standard gravity (1G) and simulated microgravity attained by using the 3D-clinostat. After 7 days of culture, the rBMSCs were analyzed morphologically, with RT-PCR and immunostaining, and were used for grafting. Adult rats were used for constructing SCI models by using a weight-dropping method and were grouped into three experimental groups for comparison. rBMSCs cultured under 1 g and simulated microgravity were transplanted intravenously immediately after SCI. We evaluated the hindlimb functional improvement for 3 weeks. Tissue repair after SCI was examined by calculating the cavity area ratio and immunohistochemistry.
  
  
  RESULTS
  rBMSCs cultured under simulated microgravity expressed Oct-4 and CXCR4, in contrast to those cultured under 1 g conditions. Therefore, rBMSCs cultured under simulated microgravity were considered to be in an undifferentiated state and thus to possess high migration ability. After transplantation, grafted rBMSCs cultured under microgravity exhibited greater survival at the periphery of the lesion, and the motor functions of the rats that received these grafts improved significantly compared with the rats that received rBMSCs cultured in 1 g. In addition, rBMSCs cultured under microgravity were thought to have greater trophic effects on reestablishment and survival of host spinal neural tissues because cavity formations were reduced, and apoptosis-inhibiting factor expression was high at the periphery of the SCI lesion.
  
  
  CONCLUSIONS
  Here we show that transplantation of rBMSCs cultured under simulated microgravity facilitates functional recovery from SCI rather than those cultured under 1 g conditions.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mitsuhara
authors.forename: Masaaki
authors.initials: M
authors.lastname: Takeda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Manabe
authors.forename: Masaya
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawahara
authors.forename: Louis
authors.initials: L
authors.lastname: Yuge
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kurisu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D018929:Cell Culture Techniques; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009043:Motor Activity; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000628:therapy*; D014893:Weightlessness
chemical_list: D050814:Octamer Transcription Factor-3; D012333:RNA, Messenger; D019718:Receptors, CXCR4
references.citation: Exp Neurol. 1996 Jun;139(2):244-56
references.pmid: 8654527
references.citation: J Neurotrauma. 2001 Nov;18(11):1267-78
references.pmid: 11721745
references.citation: PLoS One. 2009 Jul 23;4(7):e6343
references.pmid: 19626124
references.citation: J Neurosci Res. 2007 Aug 15;85(11):2332-42
references.pmid: 17549731
references.citation: Science. 1999 Feb 5;283(5403):845-8
references.pmid: 9933168
references.citation: Ann N Y Acad Sci. 2007 Dec;1122:95-111
references.pmid: 18077567
references.citation: Mol Med. 2006 Jan-Mar;12(1-3):34-46
references.pmid: 16838066
references.citation: Exp Neurol. 2004 Jun;187(2):266-78
references.pmid: 15144853
references.citation: Neurosci Lett. 2011 Jul 1;498(1):15-9
references.pmid: 21539892
references.citation: Int J Dev Neurosci. 2000 Dec;18(8):869-85
references.pmid: 11154856
references.citation: Behav Brain Res. 2007 Apr 16;179(1):118-25
references.pmid: 17324477
references.citation: J Neurosurg Spine. 2008 Feb;8(2):153-62
references.pmid: 18248287
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2199-204
references.pmid: 11854516
references.citation: J Cereb Blood Flow Metab. 2007 Jan;27(1):6-13
references.pmid: 16596121
references.citation: Exp Neurol. 2004 Nov;190(1):17-31
references.pmid: 15473977
references.citation: Neurosurgery. 2003 Sep;53(3):697-702; discussion 702-3
references.pmid: 12943585
references.citation: J Neurosci. 2005 May 11;25(19):4694-705
references.pmid: 15888645
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14069-74
references.pmid: 16172374
references.citation: In Vitro Cell Dev Biol Anim. 2003 Jan-Feb;39(1-2):89-97
references.pmid: 12892532
references.citation: Stroke. 2004 Nov;35(11 Suppl 1):2691-4
references.pmid: 15459434
references.citation: Stem Cells Dev. 2011 May;20(5):893-900
references.pmid: 20828292
references.citation: Spine (Phila Pa 1976). 2005 May 15;30(10):1154-8
references.pmid: 15897829
references.citation: PLoS One. 2009 Nov 06;4(11):e7706
references.pmid: 19893739
references.citation: J Neurotrauma. 2007 Jun;24(6):1026-36
references.pmid: 17600518
references.citation: J Neurosci. 2003 Nov 5;23(31):10107-15
references.pmid: 14602826
references.citation: Acta Histochem. 2000 Aug;102(3):273-80
references.pmid: 10990065
references.citation: Brain Res. 2010 May 21;1332:32-47
references.pmid: 20307513
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14638-43
references.pmid: 18794523
references.citation: J Neurotrauma. 1995 Feb;12(1):1-21
references.pmid: 7783230
references.citation: Neurochem Res. 2011 Nov;36(11):2063-74
references.pmid: 21748659
references.citation: Curr Opin Biotechnol. 2007 Oct;18(5):434-40
references.pmid: 18023336
references.citation: Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1167-80
references.pmid: 16897366
references.citation: Stem Cells. 2004;22(3):415-27
references.pmid: 15153618
references.citation: J Clin Invest. 2004 Jun;113(12):1701-10
references.pmid: 15199405
references.citation: Biochim Biophys Acta. 2005 Mar 22;1743(1-2):130-40
references.pmid: 15777848
references.citation: Neurosci Lett. 2009 Sep 29;463(1):54-9
references.pmid: 19628020
references.citation: J Neurochem. 2007 Sep;102(5):1459-1465
references.pmid: 17697047
references.citation: Stem Cells Dev. 2006 Dec;15(6):921-9
references.pmid: 17253953
references.citation: J Neuropathol Exp Neurol. 2004 Jan;63(1):64-72
references.pmid: 14748562
references.citation: Exp Neurol. 2000 Aug;164(2):247-56
references.pmid: 10915564
references.citation: Neuroreport. 2000 Sep 11;11(13):3001-5
references.pmid: 11006983
references.citation: Stem Cell Res Ther. 2012 Jul 09;3(4):24
references.pmid: 22776143
references.citation: Exp Hematol. 2004 Aug;32(8):773-81
references.pmid: 15308329
references.citation: J Neurol Sci. 2004 Apr 15;219(1-2):107-17
references.pmid: 15050446