Exosomes derived from P2X7 receptor gene-modified cells rescue inflammation-compromised periodontal ligament stem cells from dysfunction.
P2X7 receptor
cell exosomes
gene therapy
inflammation
microenvironment
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:
11 2020
11 2020
Historique:
received:
05
12
2019
revised:
24
04
2020
accepted:
30
05
2020
pubmed:
1
7
2020
medline:
3
9
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
Although cellular therapy has been proposed for inflammation-related disorders such as periodontitis for decades, clinical application has been unsuccessful. One explanation for these disappointing results is that the functions of stem cells are substantially compromised when they are transplanted into an inflammatory in vivo milieu. Considering the previous finding that P2X7 receptor (P2X7R) gene modification is able to reverse inflammation-mediated impairment of periodontal ligament stem cells (PDLSCs), we further hypothesized that cells subjected to P2X7R gene transduction also exert influences on other cells within an in vivo milieu via an exosome-mediated paracrine mechanism. To define the paracrine ability of P2X7R gene-modified cells, P2X7R gene-modified stem cell-derived conditional medium (CM-Ad-P2X7) and exosomes (Exs-Ad-P2X7) were used to incubate PDLSCs. In an inflammatory osteogenic microenvironment, inflammation-mediated changes in PDLSCs were substantially reduced, as shown by quantitative real-time PCR (qRT-PCR) analysis, Western blot analysis, alkaline phosphatase (ALP) staining/activity assays, and Alizarin red staining. In addition, the Agilent miRNA microarray system combined with qRT-PCR analysis revealed that miR-3679-5p, miR-6515-5p, and miR-6747-5p were highly expressed in Exs-Ad-P2X7. Further functional tests and luciferase reporter assays revealed that miR-3679-5p and miR-6747-5p bound directly to the GREM-1 protein, while miR-6515-5p bound to the GREM-1 protein indirectly; these effects combined to rescue inflammation-compromised PDLSCs from dysfunction. Thus, in addition to maintaining their robust functionality under inflammatory conditions, P2X7R gene-modified stem cells may exert positive influences on their neighbors via a paracrine mechanism, pointing to a novel strategy for modifying the harsh local microenvironment to accommodate stem cells and promote improved tissue regeneration.
Identifiants
pubmed: 32597574
doi: 10.1002/sctm.19-0418
pmc: PMC7581448
doi:
Substances chimiques
Receptors, Purinergic P2X7
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1414-1430Informations de copyright
© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.
Références
Mol Ther. 2015 Aug;23(8):1349-1357
pubmed: 26050992
Exp Cell Res. 2016 Nov 15;349(1):152-161
pubmed: 27737733
Nanomedicine. 2014 Oct;10(7):1517-27
pubmed: 24685946
Development. 2004 Jul;131(14):3401-10
pubmed: 15201225
Bone. 2012 Sep;51(3):389-400
pubmed: 22749889
Science. 1996 May 3;272(5262):735-8
pubmed: 8614837
Cytometry A. 2018 Jan;93(1):93-103
pubmed: 28678424
Nat Commun. 2018 Jun 1;9(1):2143
pubmed: 29858571
Curr Osteoporos Rep. 2018 Feb;16(1):1-12
pubmed: 29335833
Arch Oral Biol. 2020 Jan;109:104584
pubmed: 31630006
Int J Mol Sci. 2016 Dec 02;17(12):
pubmed: 27918449
Cell. 2009 Feb 20;136(4):642-55
pubmed: 19239886
Tissue Eng Part B Rev. 2019 Feb;25(1):78-88
pubmed: 30156475
Nat Genet. 2003 Jul;34(3):303-7
pubmed: 12808456
J Dent Res. 2012 Dec;91(12):1103-9
pubmed: 23042126
PLoS One. 2009;4(3):e4722
pubmed: 19266099
Annu Rev Physiol. 2015;77:13-27
pubmed: 25293529
Front Physiol. 2012 Sep 06;3:359
pubmed: 22973239
Cell Death Dis. 2013 Feb 28;4:e510
pubmed: 23449446
Oral Dis. 2018 Jul;24(5):696-705
pubmed: 28636235
Cells. 2019 Feb 03;8(2):
pubmed: 30717449
J Oral Pathol Med. 2018 Feb;47(2):206-210
pubmed: 29149498
J Cell Biochem. 2014 Jun;115(6):1138-46
pubmed: 24851271
Arch Oral Biol. 2017 Sep;81:131-135
pubmed: 28528307
Nat Biotechnol. 2011 Apr;29(4):341-5
pubmed: 21423189
Sci Rep. 2017 Mar 31;7(1):516
pubmed: 28364128
Stem Cells Int. 2018 Apr 15;2018:8973613
pubmed: 29760738
Cell Death Dis. 2018 Apr 24;9(5):480
pubmed: 29691366
Curr Opin Organ Transplant. 2012 Dec;17(6):670-4
pubmed: 23111645
FASEB J. 2017 Dec;31(12):5592-5608
pubmed: 28842429
J Immunol. 1997 Aug 1;159(3):1451-8
pubmed: 9233643
Periodontol 2000. 2019 Feb;79(1):107-116
pubmed: 30892768
J Immunol. 2009 Apr 15;182(8):5052-62
pubmed: 19342685
J Bone Miner Res. 2011 Sep;26(9):2082-95
pubmed: 21638320
Lancet. 2005 Nov 19;366(9499):1809-20
pubmed: 16298220
Stem Cell Res Ther. 2016 Feb 19;7:33
pubmed: 26895633
Front Biosci. 2008 Jan 01;13:2216-30
pubmed: 17981704
Int J Oral Sci. 2019 Aug 19;11(3):23
pubmed: 31423011
Nat Cell Biol. 2007 Jun;9(6):654-9
pubmed: 17486113
Sci Rep. 2015 Nov 05;5:16099
pubmed: 26537670
Sci Rep. 2018 Feb 22;8(1):3507
pubmed: 29472582
Stem Cell Res Ther. 2016 May 25;7(1):77
pubmed: 27387974
Genes Dev. 2011 Oct 15;25(20):2173-86
pubmed: 22012620
J Extracell Vesicles. 2015 May 14;4:27066
pubmed: 25979354
J Hematol Oncol. 2015 Oct 29;8:122
pubmed: 26514126
Int J Mol Med. 2018 Oct;42(4):2107-2119
pubmed: 30085334
Stem Cells Transl Med. 2020 Nov;9(11):1414-1430
pubmed: 32597574
Nat Rev Immunol. 2009 Aug;9(8):581-93
pubmed: 19498381
J Periodontal Res. 2020 Jan;55(1):1-12
pubmed: 31378933
Cell Stem Cell. 2008 Mar 6;2(3):205-13
pubmed: 18371446
Cell Death Dis. 2019 Jan 8;10(1):20
pubmed: 30622236
Nat Med. 2003 Sep;9(9):1195-201
pubmed: 12910262
Front Immunol. 2017 Jul 24;8:862
pubmed: 28791020
J Periodontal Res. 2019 Jun;54(3):300-309
pubmed: 30511378
Stem Cell Res Ther. 2018 Sep 26;9(1):254
pubmed: 30257721
Bone. 2019 May;122:52-75
pubmed: 30772601
Int J Cardiol. 2015 Mar 1;182:349-60
pubmed: 25590961
J Cell Physiol. 2018 Jun;233(6):4423-4442
pubmed: 29159853
Stem Cells Int. 2015;2015:659890
pubmed: 26074976
J Cell Biochem. 2011 Nov;112(11):3073-8
pubmed: 21748781
Biomaterials. 2016 Dec;111:103-115
pubmed: 27728810
Osteoporos Int. 2013 Mar;24(3):949-59
pubmed: 22707062
J Periodontal Res. 2009 Apr;44(2):199-210
pubmed: 18624943
Neuropharmacology. 1997 Sep;36(9):1127-39
pubmed: 9364468