Stabilization of cell-cell adhesions prevents symmetry breaking and locks in pluripotency in 3D gastruloids.
3D gastruloids
E-CADHERIN
WNT signaling
budesonide
cell-cell adhesion
glucocorticoid receptor
glucocorticoids
locomotion
pluripotency
symmetry breaking
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 11 2022
08 11 2022
Historique:
received:
01
04
2022
revised:
26
09
2022
accepted:
27
09
2022
pubmed:
29
10
2022
medline:
15
11
2022
entrez:
28
10
2022
Statut:
ppublish
Résumé
3D embryonic stem cell (ESC) aggregates self-organize into embryo-like structures named gastruloids that recapitulate the axial organization of post-implantation embryos. Crucial in this process is the symmetry-breaking event that leads to the emergence of asymmetry and spatially ordered structures from homogeneous cell aggregates. Here, we show that budesonide, a glucocorticoid drug widely used to treat asthma, prevents ESC aggregates to break symmetry. Mechanistically, the effect of budesonide is glucocorticoid receptor independent. RNA sequencing and lineage fate analysis reveal that budesonide counteracts exit from pluripotency and modifies the expression of a large set of genes associated with cell migration, A-P axis formation, and WNT signaling. This correlates with reduced phenotypic and molecular cell heterogeneity, persistence of E-CADHERIN at the cell-cell interface, and cell aggregate compaction. Our findings reveal that cell-cell adhesion properties control symmetry breaking and cell fate transition in 3D gastruloids and suggest a potential adverse effect of budesonide on embryo development.
Identifiants
pubmed: 36306780
pii: S2213-6711(22)00462-3
doi: 10.1016/j.stemcr.2022.09.013
pmc: PMC9669408
pii:
doi:
Substances chimiques
Budesonide
51333-22-3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2548-2564Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interests E.S. and C.C. are employees of Chiesi Farmaceutici S.p.A.
Références
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):855-9
pubmed: 7846066
Development. 2014 Nov;141(22):4231-42
pubmed: 25371360
Cell Stem Cell. 2021 Nov 4;28(11):1896-1906
pubmed: 34672948
Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8263-7
pubmed: 8058792
Eur Respir J. 2019 Feb 14;53(2):
pubmed: 30464019
J Vis Exp. 2015 Nov 24;(105):
pubmed: 26650833
Nat Commun. 2016 Sep 02;7:12589
pubmed: 27586544
Development. 2017 Feb 1;144(3):365-373
pubmed: 28143843
Development. 2017 Nov 1;144(21):3894-3906
pubmed: 28951435
BMC Dev Biol. 2017 Jun 13;17(1):7
pubmed: 28610558
EMBO Rep. 2011 Jul 01;12(7):720-6
pubmed: 21617704
Physiol Rev. 2003 Jul;83(3):965-1016
pubmed: 12843413
Cell Stem Cell. 2014 May 1;14(5):617-31
pubmed: 24630794
Lancet. 2021 Sep 4;398(10303):843-855
pubmed: 34388395
Physiol Rev. 2016 Apr;96(2):409-47
pubmed: 26842265
Nature. 2020 Jun;582(7812):405-409
pubmed: 32076263
J Med Chem. 2017 Apr 27;60(8):3405-3421
pubmed: 28368581
Dev Cell. 2020 Dec 21;55(6):679-694.e11
pubmed: 33207224
Viruses. 2021 Jul 20;13(7):
pubmed: 34372616
Lancet Respir Med. 2021 Jul;9(7):763-772
pubmed: 33844996
Placenta. 2007 Jan;28(1):39-46
pubmed: 16549198
J Cell Sci. 2014 Jun 15;127(Pt 12):2603-13
pubmed: 24931943
Stem Cell Reports. 2021 Feb 9;16(2):354-369
pubmed: 33482102
J Mol Cell Biol. 2011 Apr;3(2):108-22
pubmed: 21307025
Stem Cell Reports. 2013 Oct 10;1(4):307-21
pubmed: 24319666
Am J Physiol Cell Physiol. 2010 May;298(5):C982-92
pubmed: 20164384
J Invest Dermatol. 2007 Jul;127(7):1577-84
pubmed: 17568801
Eur Respir J. 2014 Apr;43(4):1077-85
pubmed: 24232708
Cancer Res. 2019 Jul 1;79(13):3235-3250
pubmed: 31061065
Front Cell Dev Biol. 2021 Aug 12;9:728576
pubmed: 34458276
Arch Pharmacol Ther. 2021;3(2):52-65
pubmed: 34766166
Reprod Toxicol. 2021 Oct;105:72-90
pubmed: 34425190
Cell Death Differ. 2015 Jul;22(7):1094-105
pubmed: 25857264
Methods Mol Biol. 2022;2490:197-204
pubmed: 35486247
Stem Cell Reports. 2017 Jan 10;8(1):1-10
pubmed: 28017658
Elife. 2022 Apr 11;11:
pubmed: 35404233