PMID- 33763061
OWN - NLM
STAT- MEDLINE
DCOM- 20210630
LR  - 20210630
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Musculoskeletal Progenitor/Stromal Cell-Derived Mitochondria Modulate Cell 
      Differentiation and Therapeutical Function.
PG  - 606781
LID - 10.3389/fimmu.2021.606781 [doi]
LID - 606781
AB  - Musculoskeletal stromal cells' (MSCs') metabolism impacts cell differentiation as 
      well as immune function. During osteogenic and adipogenic differentiation, 
      BM-MSCs show a preference for glycolysis during proliferation but shift to an 
      oxidative phosphorylation (OxPhos)-dependent metabolism. The MSC immunoregulatory 
      fate is achieved with cell polarization, and the result is sustained production 
      of immunoregulatory molecules (including PGE2, HGF, IL1RA, IL6, IL8, IDO 
      activity) in response to inflammatory stimuli. MSCs adapt their energetic 
      metabolism when acquiring immunomodulatory property and shift to aerobic 
      glycolysis. This can be achieved via hypoxia, pretreatment with small 
      molecule-metabolic mediators such as oligomycin, or AKT/mTOR pathway modulation. 
      The immunoregulatory effect of MSC on macrophages polarization and Th17 switch is 
      related to the glycolytic status of the MSC. Indeed, MSCs pretreated with 
      oligomycin decreased the M1/M2 ratio, inhibited T-CD4 proliferation, and 
      prevented Th17 switch. Mitochondrial activity also impacts MSC metabolism. In the 
      bone marrow, MSCs are present in a quiescent, low proliferation, but they keep 
      their multi-progenitor function. In this stage, they appear to be glycolytic with 
      active mitochondria (MT) status. During MSC expansion, we observed a metabolic 
      shift toward OXPhos, coupled with an increased MT activity. An increased 
      production of ROS and dysfunctional mitochondria is associated with the metabolic 
      shift to glycolysis. In contrast, when MSC underwent chondro or osteoblast 
      differentiation, they showed a decreased glycolysis and inhibition of the pentose 
      phosphate pathway (PPP). In parallel the mitochondrial enzymatic activities 
      increased associated with oxidative phosphorylation enhancement. MSCs respond to 
      damaged or inflamed tissue through the transfer of MT to injured and immune 
      cells, conveying a type of signaling that contributes to the restoration of cell 
      homeostasis and immune function. The delivery of MT into injured cells increased 
      ATP levels which in turn maintained cellular bioenergetics and recovered cell 
      functions. MSC-derived MT may be transferred via tunneling nanotubes to 
      undifferentiated cardiomyocytes and leading to their maturation. In this review, 
      we will decipher the pathways and the mechanisms responsible for mitochondria 
      transfer and activity. The eventual reversal of the metabolic and 
      pro-inflammatory profile induced by the MT transfer will open new avenues for the 
      control of inflammatory diseases.
CI  - Copyright (c) 2021 Jorgensen and Khoury.
FAU - Jorgensen, Christian
AU  - Jorgensen C
AD  - Inserm, U1183, Montpellier, France.
AD  - Universite MONTPELLIER 1, UFR de Medecine, Montpellier, France.
AD  - Service d'immuno-Rhumatologie, Hopital Lapeyronie, Montpellier, France.
FAU - Khoury, Maroun
AU  - Khoury M
AD  - Laboratory of Nano-Regenerative Medicine, Centro de Investigacion e Innovacion 
      Biomedica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
AD  - Cells for Cells, Santiago, Chile.
AD  - Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, 
      Chile.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20210308
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Biomarkers)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Cell Culture Techniques
MH  - *Cell Differentiation
MH  - Cell- and Tissue-Based Therapy/methods
MH  - Cellular Reprogramming
MH  - Energy Metabolism
MH  - Humans
MH  - Immunomodulation
MH  - Mesenchymal Stem Cell Transplantation/methods
MH  - Mesenchymal Stem Cells/*cytology/*metabolism
MH  - Mitochondria/genetics/*metabolism
MH  - Myoblasts, Skeletal/*cytology/*metabolism
MH  - Oxidation-Reduction
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
PMC - PMC7982675
OTO - NOTNLM
OT  - immunometabolism
OT  - immunosuppression
OT  - mitochondria
OT  - musculoskeletal progenitor/stromal cells
OT  - stem cell
COIS- MK is the chief scientific officer of Cells for Cells and Regenero, the chilean 
      consortium for regenerative medicine. The remaining authors declare that the 
      research was conducted in the absence of any commercial or financial 
      relationships that could be construed as a potential conflict of interest.
EDAT- 2021/03/26 06:00
MHDA- 2021/07/01 06:00
PMCR- 2021/01/01
CRDT- 2021/03/25 06:27
PHST- 2020/09/15 00:00 [received]
PHST- 2021/01/20 00:00 [accepted]
PHST- 2021/03/25 06:27 [entrez]
PHST- 2021/03/26 06:00 [pubmed]
PHST- 2021/07/01 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.606781 [doi]
PST - epublish
SO  - Front Immunol. 2021 Mar 8;12:606781. doi: 10.3389/fimmu.2021.606781. eCollection 
      2021.