title: Caudalized human iPSC-derived neural progenitor cells produce neurons and glia but fail to restore function in an early chronic spinal cord injury model.
abstract: Neural progenitor cells (NPCs) have shown modest potential and some side effects (e.g. allodynia) for treatment of spinal cord injury (SCI). In only a few cases, however, have NPCs shown promise at the chronic stage. Given the 1.275 million people living with chronic paralysis, there is a significant need to rigorously evaluate the cell types and methods for safe and efficacious treatment of this devastating condition. For the first time, we examined the pre-clinical potential of NPCs derived from human induced pluripotent stem cells (hiPSCs) to repair chronic SCI. hiPSCs were differentiated into region-specific (i.e. caudal) NPCs, then transplanted into a new, clinically relevant model of early chronic cervical SCI. We established the conditions for successful transplantation of caudalized hiPSC-NPCs and demonstrate their remarkable ability to integrate and produce multiple neural lineages in the early chronic injury environment. In contrast to prior reports in acute and sub-acute injury models, survival and integration of hiPSC-derived neural cells in the early chronic cervical model did not lead to significant improvement in forelimb function or induce allodynia. These data indicate that while hiPSCs show promise, future work needs to focus on the specific hiPSC-derivatives or co-therapies that will restore function in the early chronic injury setting.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA 98104, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Nutt
authors.forename: Eun-Ah
authors.initials: EA
authors.lastname: Chang
authors.forename: Steven T
authors.initials: ST
authors.lastname: Suhr
authors.forename: Laura O
authors.initials: LO
authors.lastname: Schlosser
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mondello
authors.forename: Chet T
authors.initials: CT
authors.lastname: Moritz
authors.forename: Jose B
authors.initials: JB
authors.lastname: Cibelli
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation; D009043:Motor Activity / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D058953:Neural Stem Cells / Q000637:transplantation*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation
keywords: Induced pluripotent stem cells; Neural progenitor cells; Spinal cord injury
references.citation: J Neurotrauma. 2004 Oct;21(10):1371-83
references.pmid: 15672628
references.citation: PLoS One. 2009 Dec 02;4(12):e8124
references.pmid: 19956585
references.citation: Curr Opin Neurobiol. 2007 Feb;17(1):120-7
references.pmid: 17223033
references.citation: PLoS One. 2009 Nov 06;4(11):e7706
references.pmid: 19893739
references.citation: J Neurotrauma. 2006 Jan;23(1):36-54
references.pmid: 16430371
references.citation: J Cell Biol. 2010 Feb 8;188(3):305-12
references.pmid: 20142420
references.citation: Nat Biotechnol. 2011 May 22;29(6):528-34
references.pmid: 21602806
references.citation: J Neurosci Res. 2000 Apr 15;60(2):219-30
references.pmid: 10740227
references.citation: Nat Med. 2005 Sep;11(9):966-72
references.pmid: 16086023
references.citation: Eur J Neurosci. 2002 Jul;16(2):197-208
references.pmid: 12169102
references.citation: J Neurosci. 2010 Feb 3;30(5):1657-76
references.pmid: 20130176
references.citation: Cell. 2012 Sep 14;150(6):1264-73
references.pmid: 22980985
references.citation: J Neurosci Res. 1989 Oct;24(2):212-21
references.pmid: 2479764
references.citation: Exp Neurol. 2003 Aug;182(2):247-60
references.pmid: 12895437
references.citation: Exp Neurol. 1995 Jun;133(2):231-43
references.pmid: 7649228
references.citation: J Neurosci Res. 2005 Apr 15;80(2):182-90
references.pmid: 15772979
references.citation: Dev Neurosci. 2004 Mar-Aug;26(2-4):148-65
references.pmid: 15711057
references.citation: J Neurosci. 2002 Apr 15;22(8):3130-43
references.pmid: 11943816
references.citation: J Neurosci. 2005 May 11;25(19):4694-705
references.pmid: 15888645
references.citation: J Stroke Cerebrovasc Dis. 2013 May;22(4):304-8
references.pmid: 22078778
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14069-74
references.pmid: 16172374
references.citation: Epileptic Disord. 2006 Jun;8(2):91-102
references.pmid: 16793570
references.citation: Genes Dev. 2003 Jul 1;17(13):1677-89
references.pmid: 12842915
references.citation: J Clin Invest. 2011 Jun;121(6):2326-35
references.pmid: 21576821
references.citation: Neuropharmacology. 2000 Mar 3;39(5):777-87
references.pmid: 10699444
references.citation: J Neurosci. 2012 Apr 11;32(15):5120-5
references.pmid: 22496557
references.citation: J Neurosci. 2005 Oct 19;25(42):9624-36
references.pmid: 16237167
references.citation: J Neurotrauma. 2011 Aug;28(8):1611-82
references.pmid: 20146557
references.citation: J Neurosci Res. 2002 Sep 15;69(6):925-33
references.pmid: 12205685
references.citation: Nat Biotechnol. 2005 Feb;23(2):215-21
references.pmid: 15685164
references.citation: J Neural Eng. 2011 Aug;8(4):046033
references.pmid: 21753237
references.citation: Nat Protoc. 2009;4(9):1295-304
references.pmid: 19696748
references.citation: J Comp Neurol. 2003 Dec 1;467(1):1-10
references.pmid: 14574675
references.citation: FASEB J. 2005 Nov;19(13):1839-41
references.pmid: 16141363
references.citation: Spinal Cord. 2007 Mar;45(3):190-205
references.pmid: 17179973
references.citation: Nat Neurosci. 2009 Apr;12(4):399-408
references.pmid: 19287386
references.citation: Neuron. 2012 Apr 12;74(1):79-94
references.pmid: 22500632
references.citation: PLoS One. 2010 Aug 18;5(8):e12272
references.pmid: 20806064
references.citation: Nat Rev Neurosci. 2011 Feb;12(2):88-104
references.pmid: 21248788
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):146-56
references.pmid: 14735117
references.citation: Neuroscience. 2010 Apr 28;167(1):21-30
references.pmid: 20149844
references.citation: Nat Neurosci. 2003 Nov;6(11):1127-34
references.pmid: 14583753
references.citation: Nat Neurosci. 2010 Oct;13(10):1181-9
references.pmid: 20871603
references.citation: Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S2-12
references.pmid: 11805601
references.citation: PLoS One. 2011 Mar 02;6(3):e17540
references.pmid: 21407814
references.citation: Physiol Rev. 1996 Apr;76(2):319-70
references.pmid: 8618960
references.citation: Eur J Neurosci. 2005 Dec;22(12):3036-46
references.pmid: 16367770
references.citation: J Neurotrauma. 2010 Jan;27(1):21-33
references.pmid: 19751098
references.citation: Genes Cells. 2010 May;15(5):455-70
references.pmid: 20384793
references.citation: J Neurosci Res. 1989 Oct;24(2):201-11
references.pmid: 2479763
references.citation: Nat Neurosci. 2005 Mar;8(3):346-53
references.pmid: 15711542
references.citation: J Neurosci. 1999 Dec 1;19(23):10372-82
references.pmid: 10575034
references.citation: Stem Cells. 2007 Jun;25(6):1511-20
references.pmid: 17332508
references.citation: J Cell Biochem. 2008 Nov 1;105(4):949-55
references.pmid: 18668528
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12704-9
references.pmid: 20615974
references.citation: Neuroscientist. 2007 Apr;13(2):173-85
references.pmid: 17404377
references.citation: Neurotherapeutics. 2011 Oct;8(4):704-20
references.pmid: 22002087
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16825-30
references.pmid: 21949375
references.citation: Brain Behav Evol. 1997;50 Suppl 1:3-16
references.pmid: 9217990
references.citation: J Cell Physiol. 2000 Mar;182(3):311-22
references.pmid: 10653597
references.citation: Spinal Cord. 2005 Aug;43(8):453-8
references.pmid: 15824756
references.citation: J Neurophysiol. 1999 Jul;82(1):359-69
references.pmid: 10400964
references.citation: Stem Cells. 2012 Jun;30(6):1163-73
references.pmid: 22419556
references.citation: J Spinal Cord Med. 2000 Summer;23(2):111-20
references.pmid: 10914352
references.citation: Regen Med. 2011 May;6(3):367-406
references.pmid: 21548741