Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo.
Animals
Cell Differentiation
Cells, Cultured
Gene Expression Profiling
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Mice
Mice, Inbred C57BL
Organoids
/ cytology
Photoreceptor Cells, Vertebrate
/ cytology
Pluripotent Stem Cells
/ cytology
Retina
/ cytology
Signal Transduction
Transcriptome
3D organoids
RNA-seq
development
gene expression
gene regulation
iPSC
neural retina
photoreceptor differentiation
pluripotent stem cells
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
12 11 2019
12 11 2019
Historique:
received:
25
04
2019
revised:
20
09
2019
accepted:
23
09
2019
pubmed:
22
10
2019
medline:
1
7
2020
entrez:
22
10
2019
Statut:
ppublish
Résumé
Stem cell-derived retinal organoids recapitulate many landmarks of in vivo differentiation but lack functional maturation of distinct cell types, especially photoreceptors. Using comprehensive temporal transcriptome analyses, we show that transcriptome shift from postnatal day 6 (P6) to P10, associated with morphogenesis and synapse formation during mouse retina development, was not evident in organoids, and co-expression clusters with similar patterns included different sets of genes. Furthermore, network analysis identified divergent regulatory dynamics between developing retina in vivo and in organoids, with temporal dysregulation of specific signaling pathways and delayed or reduced expression of genes involved in photoreceptor function(s) and survival. Accordingly, addition of docosahexaenoic acid and fibroblast growth factor 1 to organoid cultures specifically promoted the maturation of photoreceptors, including cones. Our study thus identifies regulatory signals deficient in developing retinal organoids and provides experimental validation by producing a more mature retina in vitro, thereby facilitating investigations in disease modeling and therapies.
Identifiants
pubmed: 31631019
pii: S2213-6711(19)30338-8
doi: 10.1016/j.stemcr.2019.09.009
pmc: PMC6895716
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
891-905Subventions
Organisme : NEI NIH HHS
ID : ZIA EY000450
Pays : United States
Organisme : NEI NIH HHS
ID : ZIA EY000474
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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