PMID- 36096355
OWN - NLM
STAT- MEDLINE
DCOM- 20221018
LR  - 20221026
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 192
DP  - 2022 Nov 1
TI  - Silencing SIRT5 induces the senescence of UCB-MSCs exposed to TNF-alpha by reduction 
      of fatty acid beta-oxidation and anti-oxidation.
PG  - 1-12
LID - S0891-5849(22)00583-4 [pii]
LID - 10.1016/j.freeradbiomed.2022.09.002 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine involved in cell 
      survival, apoptosis, and homeostasis. However, the regulatory effect of TNF-alpha on 
      mesenchymal stem cell (MSC) redox regulation remains unknown. The process of 
      delaying the senescence of MSCs and maintaining antioxidation mechanism is 
      important in transplantation therapy to treat inflammatory diseases that result 
      from restricted immunomodulatory effects of senescent MSCs. Thus, we examined the 
      role of TNF-alpha-mediated signaling and its regulatory mechanisms on the senescence 
      of umbilical cord blood-derived MSCs (UCB-MSCs) and identified its therapeutic 
      efficacy in a collagen-induced arthritis (CIA) mouse model. We found that TNF-alpha 
      increased fatty acid synthesis and lipid droplet (LD) formation through 
      NF-kappaB/SREBP1-mediated FASN, SCD1, and DGAT2 expression, which protects UCB-MSCs 
      from oxidative stress against accumulated toxic lipids. Additionally, 
      DGAT2-mediated LD formation was regulated by TNF-alpha-activated TNF receptor (TNFR)1 
      signaling. We also found that storage of unsaturated FAs in LDs is regulated by 
      SIRT5-dependent beta-oxidation of FAs, which reduces mitochondrial ROS (mtROS) 
      accumulation. Particularly, mtROS homeostasis was maintained by superoxide 
      dismutase 2 (SOD2) upregulation through TNFR2-mediated SIRT5/Nrf2 signaling. In a 
      CIA mouse model, UCB-MSCs transfected with SIRT5 siRNA exhibited reduced 
      therapeutic effects compared with UCB-MSCs transfected with NT siRNA. Overall, 
      the results indicated that SIRT5 plays a central role in protecting TNF-alpha-induced 
      UCB-MSC senescence through FA beta-oxidation and SOD2-mediated antioxidation.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Jung, Young Hyun
AU  - Jung YH
AD  - Department of Veterinary Physiology, College of Veterinary Medicine, Research 
      Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine 
      Leading Education and Research Center, Seoul National University, Seoul, 08826, 
      South Korea.
FAU - Chae, Chang Woo
AU  - Chae CW
AD  - Department of Veterinary Physiology, College of Veterinary Medicine, Research 
      Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine 
      Leading Education and Research Center, Seoul National University, Seoul, 08826, 
      South Korea.
FAU - Chang, Han Seung
AU  - Chang HS
AD  - Department of Veterinary Physiology, College of Veterinary Medicine, Research 
      Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine 
      Leading Education and Research Center, Seoul National University, Seoul, 08826, 
      South Korea.
FAU - Choi, Gee Euhn
AU  - Choi GE
AD  - Laboratory of Veterinary Biochemistry, College of Veterinary Medicine, Jeju 
      National University, Jeju, 63243, South Korea.
FAU - Lee, Hyun Jik
AU  - Lee HJ
AD  - Laboratory of Veterinary Physiology, College of Veterinary Medicine, Chungbuk 
      National University, Cheongju, Chungbuk, 28644, South Korea; Institute for Stem 
      Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, 
      Chungbuk, 28644, South Korea.
FAU - Han, Ho Jae
AU  - Han HJ
AD  - Department of Veterinary Physiology, College of Veterinary Medicine, Research 
      Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine 
      Leading Education and Research Center, Seoul National University, Seoul, 08826, 
      South Korea. Electronic address: hjhan@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220909
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Cytokines)
RN  - 0 (Fatty Acids)
RN  - 0 (Lipids)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (SIRT5 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.5.1.- (Sirtuins)
SB  - IM
MH  - Animals
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Fatty Acids
MH  - Gene Silencing
MH  - Lipids
MH  - Mice
MH  - *NF-E2-Related Factor 2/genetics
MH  - NF-kappa B/metabolism
MH  - Oxidation-Reduction
MH  - RNA, Small Interfering/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type II/metabolism
MH  - *Sirtuins/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
OTO - NOTNLM
OT  - Fatty acid oxidation
OT  - Lipid droplet
OT  - Mitochondrial reactive oxygen species
OT  - SIRT5
OT  - Superoxide dismutase 2
OT  - TNF-alpha
COIS- Declaration of competing interest The authors declare no competing interests.
EDAT- 2022/09/13 06:00
MHDA- 2022/10/19 06:00
CRDT- 2022/09/12 19:26
PHST- 2022/07/07 00:00 [received]
PHST- 2022/08/30 00:00 [revised]
PHST- 2022/09/05 00:00 [accepted]
PHST- 2022/09/13 06:00 [pubmed]
PHST- 2022/10/19 06:00 [medline]
PHST- 2022/09/12 19:26 [entrez]
AID - S0891-5849(22)00583-4 [pii]
AID - 10.1016/j.freeradbiomed.2022.09.002 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2022 Nov 1;192:1-12. doi: 
      10.1016/j.freeradbiomed.2022.09.002. Epub 2022 Sep 9.