Injured inflammatory environment overrides the TET2 shaped epigenetic landscape of pluripotent stem cell derived human neural stem cells.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Dioxygenases* ; Epigenesis, Genetic* ; DNA-Binding Proteins*/metabolism ; DNA-Binding Proteins*/genetics ; Neural Stem Cells*/metabolism ; Proto-Oncogene Proteins*/metabolism ; Proto-Oncogene Proteins*/genetics ; DNA Methylation* ; Cell Differentiation*/genetics; Humans ; Spinal Cord Injuries/metabolism ; Spinal Cord Injuries/genetics ; Spinal Cord Injuries/pathology ; Pluripotent Stem Cells/metabolism ; Inflammation/genetics ; Inflammation/pathology ; Inflammation/metabolism ; Animals ; Mice

Spinal cord injury creates an inflammatory microenvironment that regulates the capacity of transplanted human Neural Stem Cells (hNSC) to migrate, differentiate, and repair injury. Despite similarities in gene expression and markers detected by immunostaining, hNSC populations exhibit heterogeneous therapeutic potential. This heterogeneity derives in part from the epigenetic landscape in the hNSC genome, specifically methylation (5mC) and hydroxymethylation (5hmC) state, which may affect the response of transplanted hNSC in the injury microenvironment and thereby modulate repair capacity. We demonstrate a significant up-regulation of methylcytosine dioxygenase 2 gene (TET2) expression in undifferentiated hNSC derived from human embryonic stem cells (hES-NSC), and report that this is associated with hES-NSC competence for differentiation marker expression. TET2 protein catalyzes active demethylation and TET2 upregulation could be a signature of pluripotent exit, while shaping the epigenetic landscape in hES-NSC. We determine that the inflammatory environment overrides epigenetic programming in vitro and in vivo by directly modulating TET2 expression levels in hES-NSC to change cell fate. We also report the effect of cell fate and microenvironment on differential methylation 5mC/5hmC balance. Understanding how the activity of epigenetic modifiers changes within the transplantation niche in vivo is crucial for assessment of hES-NSC behavior for potential clinical applications.
(© 2024. The Author(s).)

PLoS Genet. 2011 Jun;7(6):e1002154. (PMID: 21731508)
J Clin Invest. 2009 Jun;119(6):1420-8. (PMID: 19487818)
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):E8267-E8276. (PMID: 27930333)
Cell. 2012 Jun 8;149(6):1368-80. (PMID: 22608086)
Genome Biol. 2014 Feb 20;15(2):R37. (PMID: 24555846)
Nucleic Acids Res. 2016 Jul 8;44(12):5550-6. (PMID: 27257071)
Stem Cell Res. 2017 Dec;25:139-151. (PMID: 29128818)
Nat Neurosci. 2011 Oct 30;14(12):1607-16. (PMID: 22037496)
Glia. 2019 Jun;67(6):1017-1035. (PMID: 30548343)
Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1361-6. (PMID: 24474761)
Cell. 2012 Dec 21;151(7):1417-30. (PMID: 23260135)
Genome Biol. 2014 Sep 24;15(9):456. (PMID: 25248841)
Science. 2009 May 15;324(5929):929-30. (PMID: 19372393)
Nature. 2011 May 19;473(7347):394-7. (PMID: 21552279)
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14069-74. (PMID: 16172374)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Annu Rev Genomics Hum Genet. 2015;16:55-77. (PMID: 26077819)
Science. 2013 Aug 9;341(6146):1237905. (PMID: 23828890)
Brain. 2010 Feb;133(Pt 2):433-47. (PMID: 20085927)
Stem Cells. 2007 Jun;25(6):1521-8. (PMID: 17379764)
Stem Cell Res Ther. 2020 May 27;11(1):208. (PMID: 32460847)
Nucleic Acids Res. 2016 Oct 14;44(18):8682-8692. (PMID: 27288448)
Stem Cell Res. 2013 May;10(3):417-427. (PMID: 23474892)
Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7812-E7821. (PMID: 28847947)
J Neurosci Res. 2012 Oct;90(10):1883-91. (PMID: 22714992)
Trends Immunol. 2016 Sep;37(9):608-620. (PMID: 27443914)
Genome Biol. 2010;11(10):R106. (PMID: 20979621)
Epigenetics Chromatin. 2018 Oct 5;11(1):58. (PMID: 30290828)
Cell Rep. 2013 Feb 21;3(2):291-300. (PMID: 23403289)
Neuron. 2014 Jul 2;83(1):69-86. (PMID: 24991955)
Exp Neurol. 2016 Jul;281:1-16. (PMID: 27079998)
Nature. 2015 Feb 19;518(7539):344-9. (PMID: 25693565)
Chromosoma. 2012 Jun;121(3):251-62. (PMID: 22427185)
Annu Rev Neurosci. 2009;32:149-84. (PMID: 19555289)
Mol Cell. 2011 Oct 7;44(1):17-28. (PMID: 21924933)
Front Genet. 2017 Jul 19;8:100. (PMID: 28769976)
Stem Cell Res. 2014 Sep;13(2):214-26. (PMID: 25082219)
Cell. 2013 Dec 19;155(7):1545-55. (PMID: 24315485)
J Neurotrauma. 2006 May;23(5):635-59. (PMID: 16689667)
Cell Stem Cell. 2013 Sep 5;13(3):265-9. (PMID: 24012367)
Development. 2018 Mar 14;145(6):. (PMID: 29540464)
Science. 2018 Sep 28;361(6409):1336-1340. (PMID: 30262495)
Nucleic Acids Res. 2005 Oct 13;33(18):5868-77. (PMID: 16224102)
Mol Biol Rep. 2021 Jul;48(7):5735-5743. (PMID: 34304391)
J Immunol. 2017 Aug 1;199(3):1069-1085. (PMID: 28687659)
Nat Genet. 2016 Sep;48(9):1014-23. (PMID: 27428748)
Nature. 2015 Feb 19;518(7539):355-359. (PMID: 25533951)
Mol Cells. 2014 Oct 31;37(10):705-12. (PMID: 25234468)
Mol Cell. 2014 Oct 23;56(2):286-297. (PMID: 25263596)
Nat Chem. 2014 Dec;6(12):1049-55. (PMID: 25411882)
Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313)
Sci Rep. 2019 Dec 20;9(1):19565. (PMID: 31863072)
J Comp Neurol. 2014 Aug 15;522(12):2767-83. (PMID: 24715528)
Science. 2010 Jul 23;329(5990):444-8. (PMID: 20651149)
Life Sci Alliance. 2019 Apr 1;2(2):. (PMID: 30936186)
Stem Cell Reports. 2014 Apr 18;2(5):620-32. (PMID: 24936450)
Nucleic Acids Res. 2014 Apr;42(8):e69. (PMID: 24561809)
Hum Mol Genet. 2012 Dec 15;21(26):5500-10. (PMID: 23042784)
Neural Plast. 2018 Apr 18;2018:2952386. (PMID: 29849554)
Front Cell Dev Biol. 2021 Feb 18;9:645335. (PMID: 33681230)
Mol Cell. 2015 Nov 19;60(4):584-96. (PMID: 26590716)

EC 1.13.11.- (Dioxygenases)
EC 1.13.11.- (TET2 protein, human)
0 (DNA-Binding Proteins)
0 (Proto-Oncogene Proteins)

Date Created: 20241025 Date Completed: 20241025 Latest Revision: 20241028

20241028

PMC11502794

10.1038/s41598-024-75689-3

39448736