Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model

Liao, Naishun; Shi, Yonghong; Wang, Yingchao; Liao, Fangyu; Zhao, Bixing; Zheng, Youshi; Zeng, Yongyi; Liu, Xiaolong; Liu, Jingfeng

doi:10.21203/rs.3.rs-16518/v1

Cited by 7 publications

(14 citation statements)

References 21 publications

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“…Curiously, pretreatment of adipose tissue‐derived mesenchymal stem cells (ADSC) with 10 µM melatonin also demonstrated greater therapeutic effects in a murine model of liver fibrosis. This was observed by a reduction of AST, ALT, and total bilirubin levels and lower fibrotic area in mice injected with melatonin‐treated ADSC through the tail vein (Liao et al, 2020). Along with these results, melatonin improved histological parameters distinctive of liver fibrosis.…”

Section: Resultsmentioning

confidence: 98%

“…Although no melatonin measurements in plasma samples have been performed in the included studies, the highest dose employed of melatonin was 30 mg/kg (D. J. Li et al, 2019). Despite the differences in administration route, dosage, and method of fibrosis induction, melatonin is demonstrated to restrain hepatic fibrosis, improving fibrotic markers and histopathology of animal livers (Bona et al, 2018; Chen et al, 2019; Cho et al, 2015; Choi et al, 2015; Colares et al, 2016; Crespo et al, 2015; Czechowska et al, 2015; Das et al, 2017; Esrefoglu et al, 2017; González‐Fernández et al, 2017, 2018; Haeger et al, 2019; Kang et al, 2016; Lebda et al, 2018; D. J. Li et al, 2019; Liao et al, 2020; McMillin et al, 2017; Mortezaee et al, 2017, 2018; Nalobin et al, 2016; Ostrycharz et al, 2020; Renzi et al, 2011; San‐Miguel et al, 2015; Shajari et al, 2015; Stacchiotti et al, 2019; Wang et al, 2018; Wu et al, 2017; Zaitone et al, 2011). In line with this, beneficial properties of melatonin have been broadly reported in several liver pathologies, such as FHF (Laliena et al, 2012) and HCC (Carbajo‐Pescador et al, 2013; Sánchez et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence

San‐Miguel

Fernández-Palanca

Mauriz

et al. 2022

Journal Cellular Physiology

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Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N‐acetyl‐5‐methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti‐inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti‐inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence

San‐Miguel

Fernández-Palanca

Mauriz

et al. 2022

Journal Cellular Physiology

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“…Firstly, the clinic dosage needs adjustment based on the NK cell activities in patients instead of simply adopting the dosage scaled up from pre-clinic studies or used in healthy volunteers. Besides, in many liver cirrhosis clinic trials, patients have to receive repeated MSCs injections (Shi et al, 2012;Miryounesi et al, 2013;Chen et al, 2014;Jang et al, 2014;Liao et al, 2020). Our results supplied an alternative rationale for why hMSC may not work in the clinic: the accelerated clearance of hMSC in chronic liver fibrotic situations.…”

Section: Discussionmentioning

confidence: 81%

Mesenchymal Stem Cell Fates in Murine Acute Liver Injury and Chronic Liver Fibrosis Induced by Carbon Tetrachloride

Ma¹,

Liang²,

Wu³

et al. 2022

Drug Metab Dispos

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Mesenchymal stem cells (MSCs) therapy has shown potential benefits in multiple diseases. However, their clinic performance is not as satisfactory as expected. This study aimed to provide an alternative explanation by comparing MSCs' fates in different liver diseases. The distribution and therapeutic effects of hMSCs were investigated in acute liver injury (ALI) and chronic liver fibrosis (CLF) mice models, respectively. The two models were induced by single or repeated injection of carbon tetrachloride (CCl 4 ) separately. The increase of hMSCs exposure in the liver (AUC liver 0-72 h ) were more significant in ALI than in CLF (177.1% vs. 96.2%). In the ALI model, the hMSCs exposures in the lung (AUC lung 0-72 h ) increased by nearly 50% while decreased by 60.7% in CLF. The efficacy satellite study indicated that hMSCs could significantly ameliorate liver injury in ALI, but its effects in CLF were limited.In the ALI, suppressed Natural Killer (NK) cell activities were observed, while NK cell activities were increased in CLF. The depletion of NK cells could increase hMSCs exposure in mice. For mice MSC (mMSCs), their cell fates in ALI were very similar to hMSCs in ALI: mMSCs' exposure in the liver and lung increased in ALI. In conclusion, our study revealed the distinct cell pharmacokinetic patterns of MSCs in ALI and CLF mice, which might be at least partially attributed to the different NK cell activities in the two liver diseases. This finding provided a novel insight into the varied MSCs' therapeutic efficacy in the clinic.

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“…The MSCs have been reported to play an anti-brotic role in brotic diseases such as liver brosis [29], kidney brosis [30], lung brosis [31,32], and skin brosis [10]. However, there are still unresolved and unavoidable risks of MSC clinical application such as iatrogenic tumor formation, cellular rejection and infusion toxicity [33].…”

Section: Discussionmentioning

confidence: 99%

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

Jin

Wang

et al. 2021

Preprint

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BackgroundSystemic sclerosis (SSc) is a disease with severe fibrosis of the skin without effective therapy. While bone marrow mesenchymal stem cell (BMSC) derived exosome was a potential stem cell-based candidate in treatment of SSc.MethodsBMSCs were isolated from the bone marrow of mouse and identified with the surface markers and multi-lineage differentiation. The exosomes were isolated from the BMSCs culture medium with ultracentrifugation and identified with NTA, TEM and western blot. The miRNAs of the BMSC-derived exosomes (BMSC-EXOs) were studied via miRNA sequencing and bioinformatic analysis. The SSc model was established in mice by bleomycin (BLM) subcutaneous injection and the mice were treated with BMSCs or BMSC-derived exosomes. The skin tissues were dissociated and analyzed with H&E staining, RNA sequencing and immunohistochemical staining.ResultsEvident pathological changes like fibrosis and inflammation induced in the skin of BLM-treated mice. Both BMSCs and BMSC-EXOs effectively intervened such pathological manifestations and disease process, in a very similar way. The effects of the BMSC-EXOs were tracked to their microRNAs, which were proved to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple biological processes when the EXOs functioned. Furthermore, the TGF-β1 positive cells and α-SMA positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice, but evidently reduced in the EXO-treated SSc group. Meanwhile, the number of mast cells as well as the infiltrated macrophages and lymphocytes were evidently increased in the skins of the BLM-treated mice, but significantly reduced by the EXO treatment. Such observations were confirmed by the data of the detected inflammatory cytokines that significantly higher mRNA levels of Il6, Il10 and Tnf-α were found in SSc mice, but reduced following the EXO treatment. Through bioinformatics analysis, TGFβ and WNT signaling pathways were revealed to be closely involved in the pathogenic changes in mouse SSc and could be the main targets for treating the disease.ConclusionsBMSC-derived exosomes could be developed as a potential therapy for treating the dysfunction of the skin in SSc, especially for its similar efficacy with BMSCs but less regulated as compared to cell therapy. Its mechanisms are involved in its microRNAs which alleviate the SSc pathogenic changes through regulating WNT and TGFβ signaling pathways.

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Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model

Cited by 7 publications

References 21 publications

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence

Mesenchymal Stem Cell Fates in Murine Acute Liver Injury and Chronic Liver Fibrosis Induced by Carbon Tetrachloride

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

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