TY - JOUR
T1 - Musculoskeletal Progenitor/Stromal Cell-Derived Mitochondria Modulate Cell Differentiation and Therapeutical Function
AU - Jorgensen, Christian
AU - Khoury, Maroun
N1 - Funding Information:
This work was supported by grants from National Agency for Investigation and Development: ANID (Agencia Nacional de Investigación y Desarrollo) [FONDECYT regular #1170852, #1201420 and #1211749].
Publisher Copyright:
© Copyright © 2021 Jorgensen and Khoury.
Copyright © 2021 Jorgensen and Khoury.
PY - 2021/3/8
Y1 - 2021/3/8
N2 - 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.
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.
KW - immunometabolism
KW - immunosuppression
KW - mitochondria
KW - musculoskeletal progenitor/stromal cells
KW - stem cell
KW - Reactive Oxygen Species/metabolism
KW - Myoblasts, Skeletal/cytology
KW - Oxidation-Reduction
KW - Signal Transduction
KW - Immunomodulation
KW - Cell- and Tissue-Based Therapy/methods
KW - Humans
KW - Mesenchymal Stem Cell Transplantation/methods
KW - Mesenchymal Stem Cells/cytology
KW - Cellular Reprogramming
KW - Animals
KW - Energy Metabolism
KW - Mitochondria/genetics
KW - Biomarkers
KW - Cell Differentiation
KW - Cell Culture Techniques
KW - Immunometabolism
KW - immunosuppression
KW - mitochondria
KW - musculoskeletal progenitor/stromal cells
KW - Stem cell
UR - http://www.scopus.com/inward/record.url?scp=85102941237&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/adb32e23-726f-39fe-9a94-909a1d760b7c/
U2 - 10.3389/fimmu.2021.606781
DO - 10.3389/fimmu.2021.606781
M3 - Article
C2 - 33763061
AN - SCOPUS:85102941237
SN - 1664-3224
VL - 12
SP - 606781
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 606781
ER -