Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes.
ATAC-seq
CDX2
RNA-seq
development
fetal pancreas
gene regulatory network
human pluripotent stem cells
islets
pancreas
serotonin
signals
single-cell genomics
transcription factors
β cell
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
08 05 2023
08 05 2023
Historique:
received:
11
06
2022
revised:
06
01
2023
accepted:
14
03
2023
pmc-release:
08
05
2024
medline:
11
5
2023
pubmed:
12
4
2023
entrez:
11
4
2023
Statut:
ppublish
Résumé
Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.
Identifiants
pubmed: 37040771
pii: S1534-5807(23)00107-7
doi: 10.1016/j.devcel.2023.03.011
pmc: PMC10175223
mid: NIHMS1892266
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
727-743.e11Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK105541
Pays : United States
Organisme : NIDDK NIH HHS
ID : UH3 DK122639
Pays : United States
Organisme : NIDDK NIH HHS
ID : UG3 DK122639
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK120429
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK068471
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests K.J.G. does consulting for Genentech and holds stock in Vertex Pharmaceuticals.
Références
Development. 2018 Aug 15;145(16):
pubmed: 30042179
Diabetes. 2010 Jul;59(7):1674-85
pubmed: 20413507
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1607-11
pubmed: 10677506
Cell Stem Cell. 2020 Jan 2;26(1):108-122.e10
pubmed: 31839570
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12236-41
pubmed: 12221286
Mol Cell. 2018 Sep 6;71(5):858-871.e8
pubmed: 30078726
Diabetes. 2019 Jul;68(7):1394-1402
pubmed: 31127054
J Clin Invest. 2021 Dec 15;131(24):
pubmed: 34907913
Front Endocrinol (Lausanne). 2019 Feb 26;10:52
pubmed: 30863363
Diabetologia. 2011 Mar;54(3):594-604
pubmed: 21240476
Diabetes. 2020 Feb;69(2):205-214
pubmed: 31806625
Nat Genet. 2021 Apr;53(4):455-466
pubmed: 33795864
Front Endocrinol (Lausanne). 2021 Jul 16;12:689845
pubmed: 34335468
Cell Metab. 2020 May 5;31(5):1004-1016.e5
pubmed: 32375022
Trends Endocrinol Metab. 2021 Jul;32(7):474-487
pubmed: 34030925
Nat Commun. 2015 Sep 02;6:8084
pubmed: 26330140
Nat Metab. 2020 Dec;2(12):1443-1458
pubmed: 33257854
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19420-5
pubmed: 24218571
Nature. 1997 Mar 27;386(6623):399-402
pubmed: 9121556
Diabetes. 2013 May;62(5):1569-80
pubmed: 23305647
FASEB J. 2017 Sep;31(9):4140-4152
pubmed: 28592636
Lancet. 1968 Oct 5;2(7571):755-6
pubmed: 4175553
Mol Metab. 2019 Jul;25:95-106
pubmed: 31023625
Diabetes Obes Metab. 2016 Sep;18 Suppl 1:63-70
pubmed: 27615133
Nature. 2022 Feb;602(7895):112-116
pubmed: 35046577
Cell Metab. 2019 Mar 5;29(3):539-544
pubmed: 30581120
Cell Syst. 2016 Oct 26;3(4):346-360.e4
pubmed: 27667365
Endocrinology. 2012 Feb;153(2):592-601
pubmed: 22166979
Nucleic Acids Res. 2020 Jan 8;48(D1):D87-D92
pubmed: 31701148
Diabetologia. 2011 Mar;54(3):583-93
pubmed: 21190012
J Clin Invest. 2019 Jul 2;129(10):4124-4137
pubmed: 31265435
Nat Med. 2016 Mar;22(3):306-11
pubmed: 26808346
Genome Biol. 2018 Feb 6;19(1):15
pubmed: 29409532
Nat Biotechnol. 2014 Nov;32(11):1121-33
pubmed: 25211370
Nat Methods. 2017 Oct;14(10):979-982
pubmed: 28825705
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
Cell. 2014 Oct 9;159(2):428-39
pubmed: 25303535
Development. 2016 Jul 15;143(14):2616-28
pubmed: 27287799
Nat Commun. 2021 May 25;12(1):3144
pubmed: 34035279
Science. 2015 Nov 6;350(6261):aac4250
pubmed: 26542580
Cell Res. 2021 Aug;31(8):886-903
pubmed: 33692492
Nature. 2022 Oct 5;:
pubmed: 36198796
Nat Biotechnol. 2019 Aug;37(8):925-936
pubmed: 31375813
Sci Rep. 2021 Apr 22;11(1):8800
pubmed: 33888791
Stem Cell Reports. 2019 Feb 12;12(2):351-365
pubmed: 30661993
Science. 2020 Nov 13;370(6518):
pubmed: 33184180
Nat Biotechnol. 2022 Jul;40(7):1042-1055
pubmed: 35241836
Diabetes. 1988 Mar;37(3):286-91
pubmed: 3286329
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Diabetes. 2018 May;67(5):911-922
pubmed: 29500314
Diabetes. 2018 Sep;67(9):1783-1794
pubmed: 29950394
J Theor Biol. 2017 Oct 7;430:32-44
pubmed: 28652000
Front Endocrinol (Lausanne). 2021 May 05;12:635405
pubmed: 34025576
Dev Cell. 2015 Mar 9;32(5):535-45
pubmed: 25662175
Cell Death Dis. 2016 Jun 23;7(6):e2272
pubmed: 27336716
Biochim Biophys Acta. 2012 Oct;1823(10):1841-6
pubmed: 22721719
Nat Biotechnol. 2012 Feb 26;30(3):261-4
pubmed: 22371083
Nat Methods. 2017 Oct;14(10):975-978
pubmed: 28825706
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Diabetes. 2015 Jul;64(7):2497-505
pubmed: 25650326
Nat Methods. 2017 Sep 29;14(10):935-936
pubmed: 28960196
JCI Insight. 2022 Nov 8;7(21):
pubmed: 36107617
Cell Metab. 2019 Mar 5;29(3):745-754.e4
pubmed: 30449685
Metabolism. 2016 Mar;65(3):54-63
pubmed: 26892516
Sci Rep. 2019 Jun 27;9(1):9354
pubmed: 31249361
Proc Natl Acad Sci U S A. 1989 Jun;86(12):4505-9
pubmed: 2543980
Nat Methods. 2021 Mar;18(3):283-292
pubmed: 33589836
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W187-91
pubmed: 24799436
Diabetes. 2013 Oct;62(10):3459-68
pubmed: 23775765
Sci Rep. 2019 Mar 26;9(1):5233
pubmed: 30914743
J Diabetes Investig. 2018 Mar;9(2):270-273
pubmed: 28597607
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
J Clin Invest. 2023 Apr 17;133(8):
pubmed: 36821378
Nature. 2019 May;569(7756):368-373
pubmed: 31068696
Nat Med. 2010 Jul;16(7):804-8
pubmed: 20581837
Diabetes. 1972;21(2 Suppl):511-34
pubmed: 4559917
Philos Trans R Soc Lond B Biol Sci. 2016 Feb 19;371(1688):20150115
pubmed: 26833836
Cell Rep. 2020 Aug 25;32(8):108067
pubmed: 32846125
Nature. 2021 Oct;598(7879):129-136
pubmed: 34616068
Stem Cell Reports. 2015 Apr 14;4(4):591-604
pubmed: 25843049
Cell Metab. 2016 May 10;23(5):909-20
pubmed: 27133132
Nature. 2010 Feb 11;463(7282):775-80
pubmed: 20148032
Dev Biol. 1972 Dec;29(4):436-67
pubmed: 4570759
Cell Stem Cell. 2015 Jun 4;16(6):613-25
pubmed: 26046761
Nat Biotechnol. 2020 Apr;38(4):460-470
pubmed: 32094658
Nat Commun. 2021 Nov 17;12(1):6636
pubmed: 34789735
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Cell Metab. 2014 Feb 4;19(2):259-71
pubmed: 24506867
Cell Rep. 2018 Mar 6;22(10):2667-2676
pubmed: 29514095
Arch Int Physiol Biochim Biophys. 1992 Mar-Apr;100(2):127-31
pubmed: 1379488
Sci Transl Med. 2020 Apr 29;12(541):
pubmed: 32350130
Nat Commun. 2020 Feb 13;11(1):866
pubmed: 32054859
Stem Cell Reports. 2015 Dec 8;5(6):1081-1096
pubmed: 26677767
Diabetes. 2013 Apr;62(4):1227-37
pubmed: 23274896
Diabetologia. 1971 Aug;7(4):266-82
pubmed: 4106080
Genes Dev. 1997 Jul 1;11(13):1662-73
pubmed: 9224716
J Steroid Biochem Mol Biol. 2008 Jul;111(1-2):80-6
pubmed: 18556192
Diabetes. 2018 Jul;67(7):1322-1331
pubmed: 29625991
Pediatrics. 1969 Jul;44(1):76-83
pubmed: 5795407
Nat Cell Biol. 2019 Feb;21(2):263-274
pubmed: 30710150