Neuron-Glia Interactions Increase Neuronal Phenotypes in Tuberous Sclerosis Complex Patient iPSC-Derived Models.
autism
co-culture
glia
iPSC
in vitro model
myelin
neuron
neuronal activity
oligodendrocyte
tuberous sclerosis complex
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
08 01 2019
08 01 2019
Historique:
received:
16
03
2018
revised:
21
11
2018
accepted:
22
11
2018
pubmed:
26
12
2018
medline:
28
2
2020
entrez:
25
12
2018
Statut:
ppublish
Résumé
Tuberous sclerosis complex (TSC) is a rare neurodevelopmental disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes, leading to a hyperactivated mammalian target of rapamycin (mTOR) pathway, and gray and white matter defects in the brain. To study the involvement of neuron-glia interactions in TSC phenotypes, we generated TSC patient induced pluripotent stem cell (iPSC)-derived cortical neuronal and oligodendrocyte (OL) cultures. TSC neuron mono-cultures showed increased network activity, as measured by calcium transients and action potential firing, and increased dendritic branching. However, in co-cultures with OLs, neuronal defects became more apparent, showing cellular hypertrophy and increased axonal density. In addition, TSC neuron-OL co-cultures showed increased OL cell proliferation and decreased OL maturation. Pharmacological intervention with the mTOR regulator rapamycin suppressed these defects. Our patient iPSC-based model, therefore, shows a complex cellular TSC phenotype arising from the interaction of neuronal and glial cells and provides a platform for TSC disease modeling and drug development.
Identifiants
pubmed: 30581017
pii: S2213-6711(18)30488-0
doi: 10.1016/j.stemcr.2018.11.019
pmc: PMC6335594
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
42-56Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100202
Pays : United Kingdom
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Ann Neurol. 2008 Apr;63(4):444-53
pubmed: 18389497
Epilepsia. 2014 Apr;55(4):539-50
pubmed: 24512506
J Eur Acad Dermatol Venereol. 2016 Apr;30(4):586-94
pubmed: 26403211
Anal Biochem. 2013 Feb 15;433(2):105-11
pubmed: 23085117
J Exp Med. 2017 Mar 6;214(3):681-697
pubmed: 28183733
Curr Neuropharmacol. 2012 Dec;10(4):404-15
pubmed: 23730262
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3191-5
pubmed: 7512727
Mol Neurobiol. 2006 Dec;34(3):205-19
pubmed: 17308353
Hum Mol Genet. 2011 Feb 1;20(3):445-54
pubmed: 21062901
AJNR Am J Neuroradiol. 2000 Mar;21(3):557-60
pubmed: 10730651
J Cell Sci. 2006 Nov 1;119(Pt 21):4381-9
pubmed: 17074832
J Neurosurg Pediatr. 2015 Aug;16(2):134-7
pubmed: 25978531
Nat Commun. 2016 Jul 15;7:12185
pubmed: 27416896
Eur J Paediatr Neurol. 2002;6(1):15-23
pubmed: 11993952
Am J Pathol. 2018 Jan;188(1):39-52
pubmed: 29024633
Drugs. 2016 Apr;76(5):551-65
pubmed: 26927950
Genes Dev. 2008 Sep 15;22(18):2485-95
pubmed: 18794346
Stem Cell Reports. 2017 Apr 11;8(4):883-893
pubmed: 28344003
J Nucl Med. 2011 Apr;52(4):497-500
pubmed: 21421716
Ann Clin Transl Neurol. 2015 Oct 27;2(12):1041-54
pubmed: 26734657
J Neurosci. 2014 Mar 26;34(13):4453-65
pubmed: 24671992
Mol Cell Neurosci. 2018 Oct;92:149-163
pubmed: 30144504
Epilepsia. 2014 Jul;55(7):1025-9
pubmed: 24917535
J Neurosci. 2014 Jun 18;34(25):8432-48
pubmed: 24948799
Cell Rep. 2016 Apr 5;15(1):86-95
pubmed: 27052171
J Clin Invest. 2017 Sep 1;127(9):3271-3280
pubmed: 28862639
J Clin Invest. 1999 Sep;104(6):687-95
pubmed: 10491404
Glia. 2012 Nov;60(11):1684-95
pubmed: 22836368
Ann Neurol. 2012 Apr;71(4):539-51
pubmed: 22447678
Neuron. 2013 May 8;78(3):510-22
pubmed: 23664616
Trends Cell Biol. 2013 Dec;23(12):644-51
pubmed: 23988427
Front Mol Neurosci. 2014 Mar 14;7:18
pubmed: 24672426
J Neurosci. 2007 May 23;27(21):5546-58
pubmed: 17522300
J Cell Biol. 1999 Dec 13;147(6):1123-8
pubmed: 10601327
Cell Metab. 2014 Mar 4;19(3):373-9
pubmed: 24508508
Sci Rep. 2014 Jun 03;4:5155
pubmed: 24889507
Cancer Res. 2003 Dec 1;63(23):8451-60
pubmed: 14679009
Biochem J. 2008 Jun 1;412(2):179-90
pubmed: 18466115
Neurobiol Dis. 2012 Jan;45(1):369-80
pubmed: 21907282
J Pediatr Health Care. 2007 Mar-Apr;21(2):108-14
pubmed: 17321910
Am J Hum Genet. 1999 May;64(5):1305-15
pubmed: 10205261
Ann Neurol. 2007 Feb;61(2):139-52
pubmed: 17279540
Anal Biochem. 2014 Dec 15;467:1-3
pubmed: 25193447
PLoS One. 2017 Jun 6;12(6):e0178533
pubmed: 28586384
Cell Cycle. 2011 Jul 15;10(14):2305-16
pubmed: 21670596
Mol Cell Neurosci. 2007 Mar;34(3):310-23
pubmed: 17196394
Dev Neurobiol. 2016 Apr;76(4):357-74
pubmed: 26097169
J Neurosci. 2017 Aug 2;37(31):7534-7546
pubmed: 28694334
BMC Med Genet. 2011 Feb 23;12:29
pubmed: 21345208
Mol Ther. 2011 Apr;19(4):782-9
pubmed: 21285961