title: Cortical region-specific engraftment of embryonic stem cell-derived neural progenitor cells restores axonal sprouting to a subcortical target and achieves motor functional recovery in a mouse model of neonatal hypoxic-ischemic brain injury.
abstract: Hypoxic-ischemic encephalopathy (HIE) at birth could cause cerebral palsy (CP), mental retardation, and epilepsy, which last throughout the individual's lifetime. However, few restorative treatments for ischemic tissue are currently available. Cell replacement therapy offers the potential to rescue brain damage caused by HI and to restore motor function. In the present study, we evaluated the ability of embryonic stem cell-derived neural progenitor cells (ES-NPCs) to become cortical deep layer neurons, to restore the neural network, and to repair brain damage in an HIE mouse model. ES cells stably expressing the reporter gene GFP are induced to a neural precursor state by stromal cell co-culture. Forty-hours after the induction of HIE, animals were grafted with ES-NPCs targeting the deep layer of the motor cortex in the ischemic brain. Motor function was evaluated 3 weeks after transplantation. Immunohistochemistry and neuroanatomical tracing with GFP were used to analyze neuronal differentiation and axonal sprouting. ES-NPCs could differentiate to cortical neurons with pyramidal morphology and expressed the deep layer-specific marker, Ctip2. The graft showed good survival and an appropriate innervation pattern via axonal sprouting from engrafted cells in the ischemic brain. The motor functions of the transplanted HIE mice also improved significantly compared to the sham-transplanted group. These findings suggest that cortical region specific engraftment of preconditioned cortical precursor cells could support motor functional recovery in the HIE model. It is not clear whether this is a direct effect of the engrafted cells or due to neurotrophic factors produced by these cells. These results suggest that cortical region-specific NPC engraftment is a promising therapeutic approach for brain repair.
authors: Department of Neurosurgery, Yamaguchi University School of Medicine Ube, Japan.
authors: Mizuya
authors: M
authors: Shinoyama
authors: Makoto
authors: M
authors: Ideguchi
authors: Hiroyuki
authors: H
authors: Kida
authors: Koji
authors: K
authors: Kajiwara
authors: Yoshiteru
authors: Y
authors: Kagawa
authors: Yoshihiko
authors: Y
authors: Maeda
authors: Sadahiro
authors: S
authors: Nomura
authors: Michiyasu
authors: M
authors: Suzuki
keywords: Ctip2; embryonic stem cell; hypoxic-ischemic encephalopathy; integration; motor function; regeneration; transplantation
references: J Comp Neurol. 1993 Sep 1;335(1):92-108
references: 8408775
references: Mol Neurobiol. 2006 Feb;33(1):33-50
references: 16388109
references: Nat Neurosci. 2007 Oct;10(10):1294-9
references: 17828256
references: Cell Transplant. 2009;18(7):815-26
references: 19500468
references: J Neurosci Res. 2008 Jul;86(9):1936-43
references: 18335525
references: Trends Neurosci. 1990 Mar;13(3):99-104
references: 1691879
references: Clin Ther. 2006 Sep;28(9):1353-65
references: 17062309
references: Nat Biotechnol. 2002 Nov;20(11):1111-7
references: 12379868
references: Nat Biotechnol. 2003 Oct;21(10):1200-7
references: 14502203
references: Lancet. 1993 Sep 18;342(8873):742
references: 8103843
references: J Comp Neurol. 2003 Jun 9;462(3):328-41
references: 12794736
references: Brain. 2006 Dec;129(Pt 12):3238-48
references: 17018551
references: PLoS One. 2013 Jul 23;8(7):e68877
references: 23894362
references: Neuroscience. 2001;105(1):7-17
references: 11483296
references: J Neurosci. 2010 Jan 20;30(3):894-904
references: 20089898
references: Stroke. 1986 Nov-Dec;17(6):1304-8
references: 2433817
references: Ann N Y Acad Sci. 1997 Dec 19;835:234-49
references: 9616778
references: J Pediatr. 1998 Mar;132(3 Pt 2):S30-4
references: 9546034
references: Nature. 2006 Jun 29;441(7097):1087-93
references: 16810244
references: Cell Mol Life Sci. 2012 Feb;69(3):461-70
references: 21779868
references: J Neurosci. 2000 Nov 1;20(21):7994-8004
references: 11050120
references: Neuroreport. 1998 Nov 16;9(16):3703-9
references: 9858383
references: Nat Rev Neurosci. 2007 Jun;8(6):427-37
references: 17514196
references: Curr Opin Pediatr. 2000 Apr;12(2):111-5
references: 10763759
references: Eur J Neurosci. 2009 Aug;30(4):625-38
references: 19674082
references: J Pediatr. 1980 May;96(5):898-902
references: 7365599
references: Stroke. 2004 Oct;35(10):2385-9
references: 15345799
references: Lancet. 2005 Feb 19-25;365(9460):663-70
references: 15721471
references: J Neurosci. 2001 Mar 15;21(6):1931-8
references: 11245678
references: Am J Perinatol. 2000;17(3):113-20
references: 11012134
references: Stroke. 2010 Mar;41(3):516-23
references: 20075340
references: Stroke. 2001 Sep;32(9):2179-84
references: 11546914
references: Stroke. 2001 Apr;32(4):1005-11
references: 11283404
references: J Cereb Blood Flow Metab. 2008 Nov;28(11):1804-10
references: 18594556
references: J Neurosci. 2003 Apr 15;23(8):3308-15
references: 12716938
references: Trends Neurosci. 2011 Mar;34(3):124-33
references: 21316770
references: Neuron. 2006 Oct 5;52(1):39-59
references: 17015226
references: Brain Res. 2005 Jun 28;1048(1-2):116-22
references: 15921661
references: Lancet. 2001 Sep 8;358(9284):817
references: 11564497
references: Front Cell Neurosci. 2012 Mar 22;6:11
references: 22470319
references: Trends Neurosci. 2008 Apr;31(4):192-8
references: 18329734
references: N Engl J Med. 2004 Nov 4;351(19):1985-95
references: 15525724