Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions.
Bruch's membrane
age-related macular degeneration
aging
induced pluripotent stem cells
nonenzymatic nitration
retinal pigment epithelium
Journal
Stem cells translational medicine
ISSN: 2157-6580
Titre abrégé: Stem Cells Transl Med
Pays: England
ID NLM: 101578022
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
25
09
2019
accepted:
25
11
2019
pubmed:
17
12
2019
medline:
23
7
2021
entrez:
17
12
2019
Statut:
ppublish
Résumé
Modeling age-related macular degeneration (AMD) is challenging, because it is a multifactorial disease. To focus on interactions between the retinal pigment epithelium (RPE) and Bruch's membrane, we generated RPE from AMD patients and used an altered extracellular matrix (ECM) that models aged Bruch's membrane. Induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from AMD patients or age-matched (normal) controls. RPE derived from iPSCs were analyzed by morphology, marker expression, transepithelial electrical resistance (TER), and phagocytosis of rod photoreceptor outer segments. Cell attachment and viability was tested on nitrite-modified ECM, a typical modification of aged Bruch's membrane. DNA microarrays with hierarchical clustering and analysis of mitochondrial function were used to elucidate possible mechanisms for the observed phenotypes. Differentiated RPE displayed cell-specific morphology and markers. The TER and phagocytic capacity were similar among iPSC-derived RPE cultures. However, distinct clusters were found for the transcriptomes of AMD and control iPSC-derived RPE. AMD-derived iPSC-RPE downregulated genes responsible for metabolic-related pathways and cell attachment. AMD-derived iPSC-RPE exhibited reduced mitochondrial respiration and ability to attach and survive on nitrite-modified ECM. Cells that did attach induced the expression of complement genes. Despite reprogramming, iPSC derived from AMD patients yielded RPE with a transcriptome that is distinct from that of age-matched controls. When challenged with an AMD-like modification of Bruch's membrane, AMD-derived iPSC-RPE activated the complement immune system.
Identifiants
pubmed: 31840941
doi: 10.1002/sctm.19-0321
pmc: PMC7031648
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
364-376Subventions
Organisme : NEI NIH HHS
ID : P30 EY026878
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
Références
Biol Cell. 2000 Oct;92(7):477-94
pubmed: 11229600
J Biol Chem. 2014 May 23;289(21):14534-46
pubmed: 24711457
Biochim Biophys Acta. 2016 Jan;1860(1 Pt B):258-68
pubmed: 26026469
Invest Ophthalmol Vis Sci. 2013 Oct 17;54(10):6767-78
pubmed: 24030465
Genome Res. 2000 Apr;10(4):431-45
pubmed: 10779484
Brain Res. 2016 May 1;1638(Pt A):2-14
pubmed: 26706569
Nat Methods. 2015 Sep;12(9):885-92
pubmed: 26237226
Invest Ophthalmol Vis Sci. 2012 Jul 27;53(8):5016-28
pubmed: 22761260
Curr Opin Cell Biol. 2003 Oct;15(5):565-71
pubmed: 14519391
Br J Ophthalmol. 1992 Oct;76(10):607-14
pubmed: 1420043
Mech Ageing Dev. 1998 Dec 1;106(1-2):1-56
pubmed: 9883973
Transl Vis Sci Technol. 2015 Oct 30;4(5):10
pubmed: 26557417
Graefes Arch Clin Exp Ophthalmol. 1997 Jan;235(1):41-7
pubmed: 9034841
Ophthalmology. 2013 Apr;120(4):844-51
pubmed: 23332590
PLoS One. 2015 Nov 25;10(11):e0143272
pubmed: 26606685
Exp Eye Res. 2005 Jun;80(6):821-6
pubmed: 15939038
Methods Mol Biol. 2016;1390:273-85
pubmed: 26803635
Asia Pac J Ophthalmol (Phila). 2013 Jul-Aug;2(4):269-74
pubmed: 23997991
J Transl Med. 2016 Dec 20;14(1):344
pubmed: 27998274
Stem Cells Transl Med. 2013 Jul;2(7):534-44
pubmed: 23734062
Prog Retin Eye Res. 2010 Jan;29(1):1-18
pubmed: 19747980
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18277-82
pubmed: 21969589
Stem Cells Transl Med. 2020 Mar;9(3):364-376
pubmed: 31840941
Arch Ophthalmol. 1998 Mar;116(3):335-41
pubmed: 9514487
Lancet. 2018 Sep 29;392(10153):1147-1159
pubmed: 30303083
Exp Eye Res. 2019 Dec;189:107701
pubmed: 31226340
Aging (Albany NY). 2011 Apr;3(4):346-7
pubmed: 21483039
Curr Eye Res. 2002 Aug;25(2):79-89
pubmed: 12525961
Nitric Oxide. 2018 Sep 1;79:51-56
pubmed: 30055286
Redox Biol. 2017 Oct;13:255-265
pubmed: 28600982
Int J Epidemiol. 1987 Mar;16(1):31-4
pubmed: 3570619
Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4231-8
pubmed: 26161984
Invest Ophthalmol Vis Sci. 1997 May;38(6):1110-8
pubmed: 9152230
Am J Physiol Cell Physiol. 2000 Sep;279(3):C744-50
pubmed: 10942725
Clin Epigenetics. 2019 Jan 14;11(1):6
pubmed: 30642396
Connect Tissue Res. 2001 Oct;42(2):111-22
pubmed: 11718466
J Vis Exp. 2018 Apr 12;(134):
pubmed: 29708536
Epigenetics. 2015;10(8):698-707
pubmed: 26067391
Br J Ophthalmol. 2003 Feb;87(2):212-5
pubmed: 12543754
Front Aging Neurosci. 2012 May 31;4:8
pubmed: 22666212
Genome Med. 2012 Feb 24;4(2):16
pubmed: 22364233
Nat Commun. 2017 May 19;8:15374
pubmed: 28524846
Exp Eye Res. 2010 May;90(5):564-71
pubmed: 20153746
Surv Ophthalmol. 1998 May-Jun;42(6):535-47
pubmed: 9635902
J Ocul Pharmacol Ther. 2016 Jun;32(5):272-85
pubmed: 27110730
Adv Exp Med Biol. 2018;1074:29-35
pubmed: 29721924
Hum Mol Genet. 2018 Jan 1;27(1):147-159
pubmed: 29095988
J Med Chem. 2016 Jan 14;59(1):2-15
pubmed: 26322868
Stem Cell Res Ther. 2017 Oct 2;8(1):217
pubmed: 28969679
PLoS One. 2017 May 15;12(5):e0177763
pubmed: 28505174
Trans Am Ophthalmol Soc. 2003;101:499-520
pubmed: 14971591
Surv Ophthalmol. 2000 Sep-Oct;45(2):115-34
pubmed: 11033038
Invest Ophthalmol Vis Sci. 1995 Jun;36(7):1271-9
pubmed: 7775104
Cell Stem Cell. 2017 May 4;20(5):635-647.e7
pubmed: 28132833
Vet Pathol. 2010 May;47(3):396-413
pubmed: 20382825
J Cell Sci. 2003 Apr 15;116(Pt 8):1409-16
pubmed: 12640026
Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8214-E8223
pubmed: 28878022
Surv Ophthalmol. 1999 Oct;44 Suppl 1:S10-32
pubmed: 10548114
Nucleic Acids Res. 2018 Jan 4;46(D1):D661-D667
pubmed: 29136241
Trans Am Ophthalmol Soc. 2004;102:123-37; discussion 137-8
pubmed: 15747751
Front Biosci (Schol Ed). 2013 Jan 01;5:412-25
pubmed: 23277059
Exp Mol Med. 2007 Feb 28;39(1):74-83
pubmed: 17334231
Nat Immunol. 2010 Sep;11(9):785-97
pubmed: 20720586
Blood. 2010 Apr 22;115(16):3398-406
pubmed: 20023214
Invest Ophthalmol Vis Sci. 2017 Feb 1;58(2):708-719
pubmed: 28146236
Ophthalmology. 1990 Feb;97(2):171-8
pubmed: 1691475
Curr Eye Res. 2005 Aug;30(8):691-702
pubmed: 16109650
J Clin Med. 2015 Mar 31;4(4):567-78
pubmed: 26239347