Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals

Goikoetxea‐Usandizaga, Naroa; Serrano‐Maciá, Marina; Delgado, Teresa C.; Simón, Jorge; Fernández‐Ramos, David; Barriales, Diego; Cornide, M.; Jiménez, Mónica; Redondo, Marina Pérez; Lachiondo‐Ortega, Sofía; Rodríguez-Agudo, Rubén; Bizkarguenaga, Maider; Zalamea, Juan Diego; Pasco, Samuel T; Caballero‐Díaz, Daniel; Bravo, Miren; González‐Recio, Irene; Mercado-Gómez, María; Gil-Pitarch, Clàudia; Mabe, Jon; Gracia‐Sancho, Jordi; Abecia, Leticia; Lorenzo, Óscar; Martı́n-Sanz, Paloma; Abrescia, Nicola G. A.; Sabio, Guadalupe; Rincón, Mercedes; Anguíta, Juan; Miñambres, Eduardo; Martín, César San; Berenguer, Marina; Fabregat, Isabel; Casado, Marta; Peralta, Carmen A.; Varela‐Rey, Marta; Martínez‐Chantar, María Luz

doi:10.1002/hep.32149

Cited by 38 publications

(34 citation statements)

References 48 publications

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“…10,11 Of them, KCs exert significant functions in liver homeostasis, 12 hepatocellular carcinoma, 13 and liver regeneration. 14 It has been reported that F4/80 + KCs promote the proliferation of hepatocytes via releasing oncostatin, 15 while systemic depletion of KCs significantly retards the progress of liver regeneration.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, non‐parenchymal cells, such as Kupffer cells (KCs), natural killer cells (NKs), and sinusoidal endothelial cells, are involved in this process 10,11 . Of them, KCs exert significant functions in liver homeostasis, 12 hepatocellular carcinoma, 13 and liver regeneration 14 . It has been reported that F4/80 + KCs promote the proliferation of hepatocytes via releasing oncostatin, 15 while systemic depletion of KCs significantly retards the progress of liver regeneration.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxic bone marrow mesenchymal stromal cells‐derived exosomal miR ‐182‐5p promotes liver regeneration via FOXO1 ‐mediated macrophage polarization

Chen

et al. 2022

The FASEB Journal

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Mesenchymal stromal cells (MSCs) are attractive candidates for treating hepatic disorders given their potential to enhance liver regeneration and function. The paracrine paradigm may be involved in the mechanism of MSC-based therapy, and exosomes (Exo) play an important role in this paracrine activity. Hypoxia significantly improves the effectiveness of MSC transplantation. However, whether hypoxia preconditioned MSCs (Hp-MSCs) can enhance liver regeneration, and whether this enhancement is mediated by Exo, are unknown. In this study, mouse bone marrow-derived MSCs (BM-MSCs) and secreted Exo were injected through the tail vein. We report that Hp-MSCs promote liver regeneration after partial hepatectomy in mice through their secreted exosomes. Interestingly, MSC-Exo were concentrated in liver 6 h after administration and mainly taken up by macrophages, but not hepatocytes. Compared with normoxic MSC-Exo (N-Exo), hypoxic MSC-Exo (Hp-Exo) enhanced M2 macrophage polarization both in vivo and in vitro. Microarray analysis revealed significant enrichment of microRNA (miR)-182-5p in Hp-Exo compared with that in N-Exo. In addition, miR-182-5p knockdown partially abolished the beneficial effect of Hp-Exo. Finally, Hp-MSCderived exosomal miR-182-5p inhibited theprotein expression of forkhead box transcription factor 1 (FOXO1) in macrophages, which inhibited toll-like receptor Research), Grant/Award Number: 2018YFA0109800; China Postdoctoral Science Foundation, Grant/Award Number: 2019M652328 4 (TLR4) expression and subsequently induced an anti-inflammatory response. These results highlight the therapeutic potential of Hp-Exo in liver regeneration and suggest that miR-182-5p from Hp-Exo facilitates macrophage polarization during liver regeneration by modulating the FOXO1/TLR4 signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxic bone marrow mesenchymal stromal cells‐derived exosomal miR ‐182‐5p promotes liver regeneration via FOXO1 ‐mediated macrophage polarization

Chen

et al. 2022

The FASEB Journal

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“…AML12 was grown in DMEM:F12 (Thermo Fisher # 11320033) medium supplemented as instructed by supplier; HuH-7 were grown in DMEM (Thermo Fisher #12100061) and Hep-G2 in DMEM supplemented with 2 mM glutamine and 2 mM pyruvate. Primary hepatocytes were isolated from livers of 2–3-month-old wild mice by two-step collagenase perfusion method [ 34 ], seeded at 65000 cells/cm 2 in collagen-coated glass coverslips in 24-well plates and maintained in MEM supplemented with 10% FBS, 2 mM glutamine and antibiotics at 37 °C and 5% CO 2 overnight until use.…”

Section: Methodsmentioning

confidence: 99%

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver

González-Moreno¹,

Santamaría-Cano²,

Paradela³

et al. 2023

Molecular Genetics and Metabolism Reports

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“…Autophagy may be impaired during the pathogenesis of ischemic reperfusion injury (IRI), resulting in poor tolerance to IRI [ 24 ]. Strategies that reduce ROS production and liver damage, and improve mitochondrial functionality and ATP secretion could help to expand the available pool for transplantation [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Hypothermic Oxygenated Machine Perfusion Promotes Mitophagy Flux against Hypoxia-Ischemic Injury in Rat DCD Liver

Luo

Qiao

et al. 2023

IJMS

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Hypothermic oxygenated machine perfusion (HOPE) can enhance organ preservation and protect mitochondria from hypoxia-ischemic injury; however, an understanding of the underlying HOPE mechanism that protects mitochondria is somewhat lacking. We hypothesized that mitophagy may play an important role in HOPE mitochondria protection. Experimental rat liver grafts were exposed to 30 min of in situ warm ischemia. Then, grafts were procured, followed by cold storage for 3 or 4 h to mimic the conventional preservation and transportation time in donation after circulatory death (DCD) in clinical contexts. Next, the grafts underwent hypothermic machine perfusion (HMP) or HOPE for 1 h through portal vein only perfusion. The HOPE-treated group showed a better preservation capacity compared with cold storage and HMP, preventing hepatocyte damage, nuclear injury, and cell death. HOPE can increase mitophagy marker expression, promote mitophagy flux via the PINK1/Parkin pathway to maintain mitochondrial function, and reduce oxygen free radical generation, while the inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect. HOPE-treated DCD liver also demonstrated more changes in the expression of genes responsible for bile metabolism, mitochondrial dynamics, cell survival, and oxidative stress. Overall, HOPE attenuates hypoxia-ischemic injury in DCD liver by promoting mitophagy flux to maintain mitochondrial function and protect hepatocytes. Mitophagy could pave the way for a protective approach against hypoxia-ischemic injury in DCD liver.

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Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals

Cited by 38 publications

References 48 publications

Hypoxic bone marrow mesenchymal stromal cells‐derived exosomal miR ‐182‐5p promotes liver regeneration via FOXO1 ‐mediated macrophage polarization

Hypoxic bone marrow mesenchymal stromal cells‐derived exosomal miR ‐182‐5p promotes liver regeneration via FOXO1 ‐mediated macrophage polarization

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver

Hypothermic Oxygenated Machine Perfusion Promotes Mitophagy Flux against Hypoxia-Ischemic Injury in Rat DCD Liver

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