Ex vivo Ikkβ ablation rescues the immunopotency of mesenchymal stromal cells from diabetics with advanced atherosclerosis.
Aged
Animals
Atherosclerosis
/ enzymology
Case-Control Studies
Cell Proliferation
Cells, Cultured
Cellular Senescence
Coculture Techniques
Diabetes Mellitus, Type 2
/ enzymology
Disease Models, Animal
Female
Humans
I-kappa B Kinase
/ antagonists & inhibitors
Inflammation Mediators
/ metabolism
Lymphocyte Activation
Male
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells
/ drug effects
Mice, Inbred C57BL
Middle Aged
Myocardial Infarction
/ enzymology
Phenotype
Protein Kinase Inhibitors
/ pharmacology
Secretome
Signal Transduction
T-Lymphocytes
/ immunology
IKK beta signalling
Immunopotency
Inflammation
Mesenchymal stromal cells
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
22 02 2021
22 02 2021
Historique:
received:
25
03
2020
revised:
16
04
2020
accepted:
21
04
2020
pubmed:
28
4
2020
medline:
5
1
2022
entrez:
28
4
2020
Statut:
ppublish
Résumé
Diabetes is a conventional risk factor for atherosclerotic cardiovascular disease and myocardial infarction (MI) is the most common cause of death among these patients. Mesenchymal stromal cells (MSCs) in patients with type 2 diabetes mellitus (T2DM) and atherosclerosis have impaired ability to suppress activated T-cells (i.e. reduced immunopotency). This is mediated by an inflammatory shift in MSC-secreted soluble factors (i.e. pro-inflammatory secretome) and can contribute to the reduced therapeutic effects of autologous T2DM and atherosclerosis-MSC post-MI. The signalling pathways driving the altered secretome of atherosclerosis- and T2DM-MSC are unknown. Specifically, the effect of IκB kinase β (IKKβ) modulation, a key regulator of inflammatory responses, on the immunopotency of MSCs from T2DM patients with advanced atherosclerosis has not been studied. MSCs were isolated from adipose tissue obtained from patients with (i) atherosclerosis and T2DM (atherosclerosis+T2DM MSCs, n = 17) and (ii) atherosclerosis without T2DM (atherosclerosis MSCs, n = 17). MSCs from atherosclerosis+T2DM individuals displayed an inflammatory senescent phenotype and constitutively expressed active forms of effectors of the canonical IKKβ nuclear factor-κB transcription factors inflammatory pathway. Importantly, this constitutive pro-inflammatory IKKβ signature resulted in an altered secretome and impaired in vitro immunopotency and in vivo healing capacity in an acute MI model. Notably, treatment with a selective IKKβ inhibitor or IKKβ knockdown (KD) (clustered regularly interspaced short palindromic repeats/Cas9-mediated IKKβ KD) in atherosclerosis+T2DM MSCs reduced the production of pro-inflammatory secretome, increased survival, and rescued their immunopotency both in vitro and in vivo. Constitutively active IKKβ reduces the immunopotency of atherosclerosis+T2DM MSC by changing their secretome composition. Modulation of IKKβ in atherosclerosis+T2DM MSCs enhances their myocardial repair ability.
Identifiants
pubmed: 32339220
pii: 5825728
doi: 10.1093/cvr/cvaa118
pmc: PMC7898947
doi:
Substances chimiques
Inflammation Mediators
0
Protein Kinase Inhibitors
0
I-kappa B Kinase
EC 2.7.11.10
IKBKB protein, human
EC 2.7.11.10
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
756-766Subventions
Organisme : CIHR
ID : MOP-123482
Pays : Canada
Organisme : CIHR
ID : MOP 125857
Pays : Canada
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
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