PMID- 32339220
OWN - NLM
STAT- MEDLINE
DCOM- 20220104
LR  - 20240226
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 117
IP  - 3
DP  - 2021 Feb 22
TI  - Ex vivo Ikkbeta ablation rescues the immunopotency of mesenchymal stromal cells from 
      diabetics with advanced atherosclerosis.
PG  - 756-766
LID - 10.1093/cvr/cvaa118 [doi]
AB  - AIMS: 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 IkappaB kinase beta (IKKbeta) modulation, a key regulator of inflammatory responses, on 
      the immunopotency of MSCs from T2DM patients with advanced atherosclerosis has 
      not been studied. METHODS AND RESULTS: 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 IKKbeta nuclear factor-kappaB transcription factors inflammatory pathway. 
      Importantly, this constitutive pro-inflammatory IKKbeta 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 IKKbeta inhibitor 
      or IKKbeta knockdown (KD) (clustered regularly interspaced short palindromic 
      repeats/Cas9-mediated IKKbeta KD) in atherosclerosis+T2DM MSCs reduced the 
      production of pro-inflammatory secretome, increased survival, and rescued their 
      immunopotency both in vitro and in vivo. CONCLUSIONS: Constitutively active IKKbeta 
      reduces the immunopotency of atherosclerosis+T2DM MSC by changing their secretome 
      composition. Modulation of IKKbeta in atherosclerosis+T2DM MSCs enhances their 
      myocardial repair ability.
CI  - Published on behalf of the European Society of Cardiology. All rights reserved. (c) 
      The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
FAU - Kizilay Mancini, Ozge
AU  - Kizilay Mancini O
AD  - Faculty of Pharmacy, University of Montreal, C.P. 6128, Succursale Centre-Ville, 
      Montreal, QC H3C 3J7, Canada.
FAU - Huynh, David N
AU  - Huynh DN
AD  - Faculty of Pharmacy, University of Montreal, C.P. 6128, Succursale Centre-Ville, 
      Montreal, QC H3C 3J7, Canada.
FAU - Menard, Liliane
AU  - Menard L
AD  - Faculty of Pharmacy, University of Montreal, C.P. 6128, Succursale Centre-Ville, 
      Montreal, QC H3C 3J7, Canada.
FAU - Shum-Tim, Dominique
AU  - Shum-Tim D
AD  - Division of Cardiac Surgery Department of Surgery, McGill University, Montreal, 
      QC H4A 3J1, Canada.
AD  - Division of Surgical Research, Department of Surgery, McGill University, 
      Montreal, QC H4A 3J1, Canada.
FAU - Ong, Huy
AU  - Ong H
AD  - Faculty of Pharmacy, University of Montreal, C.P. 6128, Succursale Centre-Ville, 
      Montreal, QC H3C 3J7, Canada.
FAU - Marleau, Sylvie
AU  - Marleau S
AD  - Faculty of Pharmacy, University of Montreal, C.P. 6128, Succursale Centre-Ville, 
      Montreal, QC H3C 3J7, Canada.
FAU - Colmegna, Ines
AU  - Colmegna I
AD  - Division of Rheumatology, Department of Medicine, McGill University, Montreal, QC 
      H4A 3J1, Canada.
FAU - Servant, Marc J
AU  - Servant MJ
AD  - Faculty of Pharmacy, University of Montreal, C.P. 6128, Succursale Centre-Ville, 
      Montreal, QC H3C 3J7, Canada.
LA  - eng
GR  - MOP-123482/CIHR/Canada
GR  - MOP 125857/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Inflammation Mediators)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.10 (IKBKB protein, human)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Atherosclerosis/*enzymology/genetics/immunology
MH  - Case-Control Studies
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Cellular Senescence
MH  - Coculture Techniques
MH  - Diabetes Mellitus, Type 2/*enzymology/genetics/immunology
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - I-kappa B Kinase/antagonists & inhibitors/genetics/*metabolism
MH  - Inflammation Mediators/*metabolism
MH  - Lymphocyte Activation
MH  - Male
MH  - Mesenchymal Stem Cell Transplantation
MH  - Mesenchymal Stem Cells/drug effects/*enzymology/immunology
MH  - Mice, Inbred C57BL
MH  - Middle Aged
MH  - Myocardial Infarction/enzymology/immunology/surgery
MH  - Phenotype
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Secretome
MH  - Signal Transduction
MH  - T-Lymphocytes/immunology/metabolism
MH  - Mice
PMC - PMC7898947
OTO - NOTNLM
OT  - IKK beta signalling
OT  - Immunopotency
OT  - Inflammation
OT  - Mesenchymal stromal cells
EDAT- 2020/04/28 06:00
MHDA- 2022/01/05 06:00
PMCR- 2021/07/01
CRDT- 2020/04/28 06:00
PHST- 2020/03/25 00:00 [received]
PHST- 2020/04/16 00:00 [revised]
PHST- 2020/04/21 00:00 [accepted]
PHST- 2020/04/28 06:00 [pubmed]
PHST- 2022/01/05 06:00 [medline]
PHST- 2020/04/28 06:00 [entrez]
PHST- 2021/07/01 00:00 [pmc-release]
AID - 5825728 [pii]
AID - cvaa118 [pii]
AID - 10.1093/cvr/cvaa118 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2021 Feb 22;117(3):756-766. doi: 10.1093/cvr/cvaa118.