title: Factors secreted by endothelial progenitor cells enhance neurorepair responses after cerebral ischemia in mice.
abstract: Cell therapy with endothelial progenitor cells (EPCs) has emerged as a promising strategy to regenerate the brain after stroke. Here, we aimed to investigate if treatment with EPCs or their secreted factors could potentiate angiogenesis and neurogenesis after permanent focal cerebral ischemia in a mouse model of ischemic stroke. BALB/C male mice were subjected to distal occlusion of the middle cerebral artery, and EPCs, cell-free conditioned media (CM) obtained from EPCs, or vehicle media were administered one day after ischemia. Magnetic resonance imaging (MRI) was performed at baseline to confirm that the lesions were similar between groups. Immunohistochemical and histological evaluation of the brain was performed to evaluate angio-neurogenesis and neurological outcome at two weeks. CM contained growth factors, such as VEGF, FGF-b and PDGF-bb. A significant increase in capillary density was noted in the peri-infarct areas of EPC- and CM-treated animals. Bielschowsky's staining revealed a significant increase in axonal rewiring in EPC-treated animals compared with shams, but not in CM-treated mice, in close proximity with DCX-positive migrating neuroblasts. At the functional level, post-ischemia forelimb strength was significantly improved in animals receiving EPCs or CM, but not in those receiving vehicle media. In conclusion, we demonstrate for the first time that the administration of EPC-secreted factors could become a safe and effective cell-free option to be considered in future therapeutic strategies for stroke.
authors.affiliation: Neurovascular Research Laboratory, Department of Neurology and Department of Internal Medicine, Universitat Autònoma de Barcelona, Vall d'Hebron Research Institute, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.forename: Anna
authors.initials: A
authors.lastname: Morancho
authors.forename: Miriam
authors.initials: M
authors.lastname: Navarro-Sobrino
authors.forename: Elena
authors.initials: E
authors.lastname: Martínez-Saez
authors.forename: Mar
authors.initials: M
authors.lastname: Hernández-Guillamon
authors.forename: Silvia
authors.initials: S
authors.lastname: Lope-Piedrafita
authors.forename: Verónica
authors.initials: V
authors.lastname: Barceló
authors.forename: Francesc
authors.initials: F
authors.lastname: Borrás
authors.forename: Anna
authors.initials: A
authors.lastname: Penalba
authors.forename: Lidia
authors.initials: L
authors.lastname: García-Bonilla
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D017077:Culture Media, Conditioned / Q000378:metabolism; D000089662:Doublecortin Protein; D042783:Endothelial Cells / Q000166:cytology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic; D013234:Stem Cells / Q000166:cytology*; D020521:Stroke / Q000150:complications; D016896:Treatment Outcome
chemical_list: D017077:Culture Media, Conditioned; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein
references.citation: J Appl Physiol (1985). 2007 May;102(5):1927-35
references.pmid: 17234796
references.citation: Science. 1997 Feb 14;275(5302):964-7
references.pmid: 9020076
references.citation: J Exp Clin Cancer Res. 2011 Jan 17;30:9
references.pmid: 21241480
references.citation: J Clin Invest. 2004 Aug;114(3):330-8
references.pmid: 15286799
references.citation: Ann Neurol. 2010 Apr;67(4):488-97
references.pmid: 20437584
references.citation: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7505-10
references.pmid: 22529378
references.citation: Stroke. 2012 Aug;43(8):2242-4
references.pmid: 22764211
references.citation: Stem Cell Rev Rep. 2011 Mar;7(1):208-20
references.pmid: 20526754
references.citation: J Neurosurg. 2005 Jul;103(1):38-45
references.pmid: 16121971
references.citation: Transl Stroke Res. 2013 Jun;4(3):297-307
references.pmid: 24323300
references.citation: Stroke. 2011 Jan;42(1 Suppl):S16-9
references.pmid: 21164113
references.citation: Stroke. 2008 Apr;39(4):1380-8
references.pmid: 18309162
references.citation: Neurosurgery. 2006 Sep;59(3):679-86; discussion 679-86
references.pmid: 16955050
references.citation: Arterioscler Thromb Vasc Biol. 1997 Apr;17(4):605-19
references.pmid: 9108772
references.citation: Ann Neurol. 2005 Jun;57(6):874-82
references.pmid: 15929052
references.citation: Neuroscientist. 2008 Aug;14(4):369-80
references.pmid: 18024854
references.citation: Microvasc Res. 2010 Dec;80(3):317-23
references.pmid: 20594997
references.citation: Neuroimage. 2011 May 1;56(1):280-9
references.pmid: 21349337
references.citation: Brain Res. 1996 Apr 29;718(1-2):207-11
references.pmid: 8773789
references.citation: J Magn Reson Imaging. 2001 Apr;13(4):534-46
references.pmid: 11276097
references.citation: Cell Transplant. 2010;19(12):1635-44
references.pmid: 20659357
references.citation: Neuropathol Appl Neurobiol. 2012 Oct;38(6):617-27
references.pmid: 22289071
references.citation: Neuroimage. 2006 Sep;32(3):1080-9
references.pmid: 16860575
references.citation: Stroke. 2010 Jan;41(1):153-9
references.pmid: 19940279
references.citation: J Clin Invest. 2000 Oct;106(7):829-38
references.pmid: 11018070
references.citation: Regen Med. 2011 Jan;6(1):45-52
references.pmid: 21175286
references.citation: Brain Res. 2009 Jul 7;1279:121-30
references.pmid: 19427843
references.citation: J Cereb Blood Flow Metab. 2009 May;29(5):933-43
references.pmid: 19240740
references.citation: PLoS One. 2009 May 21;4(5):e5643
references.pmid: 19479066
references.citation: Circulation. 2004 Jan 27;109(3):424-31
references.pmid: 14707023
references.citation: Stem Cells. 2011 Feb;29(2):274-85
references.pmid: 21732485
references.citation: Science. 2004 May 28;304(5675):1338-40
references.pmid: 15060285
references.citation: Brain. 2011 Jun;134(Pt 6):1777-89
references.pmid: 21616972
references.citation: Swiss Med Wkly. 2010 Dec 17;140:w13130
references.pmid: 21170763
references.citation: J Neurosci. 2006 Dec 13;26(50):13007-16
references.pmid: 17167090