Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review

Shokravi, Samin; Борисов, Вячеслав Вікторович; Zaman, Burhan Abdullah; Niazvand, Firoozeh; Hazrati, Raheleh; Khah, Meysam Mohammadi; Thangavelu, Lakshmi; Marzban, Sima; Sohrabi, Armin D; Zamani, Amir

doi:10.1186/s13287-022-02825-z

Cited by 33 publications

(23 citation statements)

References 213 publications

(225 reference statements)

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“…NAC is a precursor to GSH and can increase GSH levels to reduce covalent binding between NAPQI and proteins, eliminating ROS and preserving mitochondrial energy metabolism, thus preventing liver cell necrosis and in ammation [40,43]. Research has found that MSCs from both humans and mice can increase the survival rate of mice with APAP-induced ALF [44,45].…”

Section: Discussionmentioning

confidence: 99%

3D-ESC-derived MSCs with Enhanced Immunomodulatory Capacity Repair APAP-Induced Liver Injury

Liu,

Hayierhan,

Dai

et al. 2023

Preprint

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Background Mesenchymal stem cells (MSCs) possess the ability to self-replicate, self-proliferate, and differentiate into various cell types, and hence have been extensively studied in the field of regenerative medicine. Despite the promising clinical applications of MSCs, their limited quantity and in vitro expansion potential from human tissues remain major concerns. Alternatively, MSCs can be derived from human embryonic stem cells (hESCs) that share similar phenotypic features, making hESC-MSCs a potential candidate for cell therapy. Our study aimed to investigate the efficacy of 3D-ESC-MSCs, obtained through a 3D differentiation system, as an immunoregulatory agent for treating liver damage caused by acetaminophen (APAP). Methods We differentiated human ESCs into MSCs using a 3D culture method involving a horizontal shaker. We characterized MSCs by detecting surface-specific markers through flow cytometry and qPCR, and validated their differentiation potential using in vitro lipid, bone, and cartilage differentiation assays. MSC proliferation and safety were tested using MTT, cell survival at 4°C, and nude mice tumorigenicity assays. The immune regulatory potential of 3D-ESC-MSCs was studied by transfecting polyI:C into these cells. We further investigated the effects of 3D-ESC-MSCs on APAP-induced liver injury by preconditioning hepatocyte cell line L-O2 with 3D-ESC-MSC conditioned medium and evaluating their cell viability through MTT assay. Additionally, we assessed the number of surviving cells following co-culturing with L-O2 cells stimulated with APAP. Finally, we administered 3D-ESC-MSCs to mice, via tail vein injection, with APAP-induced acute liver injury, and analyzed the repair effects by detecting ALT and AST levels in mouse serum, creating liver pathological sections, and HE staining. Results 3D-ESC-MSCs were positive for CD73, CD90, and CD105 surface markers, and negative for hematopoietic markers CD45 and HLA-DR in. The cells expressed low levels of pluripotent genes OCT4 and NANOG. Compare to umbilical cord mesenchymal stem cells (UCMSCs), 3D-ESC-MSCs displayed excellent proliferation and low-temperature resistance, and lower concentrations of polyI:C were required to induce immune regulatory genes IDO1, IF71, IRF7, and ISG15. They also exhibited higher expression levels of immunomodulatory。In vitro experiments demonstrated that the conditioned medium of 3D-ESC-MSCs increased L-O2 cell activity under low concentrations of APAP, and the survival of L-O2 cells co-cultured with 3D-ESC-MSCs was higher compared to L-02 cells cultured alone under the same conditions. Animal experiments revealed that the ALT and AST levels in APAP-treated mice injected with 3D-ESC-MSCs were reduced, and the necrotic area of the liver in the 3D-ESC-MSC group was reduced. The therapeutic effect was similar to that of the UCMSC group. Conclusions 3D-ESC-MSCs, differentiated from ESCs, exhibit stronger immunomodulatory effect and can be utilized to repair acute liver injury caused by APAP. This study highlights the clinical potential of 3D-ESC-MSCs in treating human diseases.

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Section: Discussionmentioning

confidence: 99%

3D-ESC-derived MSCs with Enhanced Immunomodulatory Capacity Repair APAP-Induced Liver Injury

Liu,

Hayierhan,

Dai

et al. 2023

Preprint

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“…Novel drug targets are being identified to combat entry of hepatotropic viruses into cells and replication such as nicotinamide in hepatitis A [ 79 ], recombinant HEV virion [ 80 ] and the newly introduced bepirovirsen in hepatitis B [ 81 ], although these are yet to be tested in acute liver failure. Emerging data from animal studies are also available on immunotherapy with agents such as thymosin alpha 1 [ 82 ], mesenchymal stem cells and their exosomes in ALF [ 83 ] as immunomodulators to prevent immune dysfunction in ALF. If successful, they would help decrease the burden on the organ pool and contribute to improving transplant free survival rates in ALF further.…”

Section: Management Of Viral Alfmentioning

confidence: 99%

Prognostic Scores in Acute Liver Failure Due to Viral Hepatitis

Biswas

Kumar

Acharya³

et al. 2023

Diagnostics

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Viral infections are among the major causes of acute liver failure (ALF) worldwide. While the role of agents such as hepatitis A, B, C, D and E viruses in precipitating ALF are well known, improvements in serological assays have led to the detection of viral agents such as Epstein Barr virus, cytomegalovirus etc. as atypical causes of ALF. Despite the plethora of literature available on viral hepatitis and ALF, there is very limited large-scale epidemiologic data on the prevalence, risk factors of progression and outcomes in ALF of viral causes. This is important as viral infections remain the leading cause of ALF in the East and in developing countries, while the impact of viral ALF in the West has largely been ameliorated by effective vaccination and sanitization programs. This review focuses specifically on the available prognostic scores that aid in the management of ALF of viral etiologies while also briefly reviewing the current literature on newer viral agents known to cause ALF, risk factors of progression, outcomes and how management algorithms can be developed by incorporation of prognostic scoring systems for referral and transplant listing.

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“…[45][46][47] MSCs exert immunomodulatory and immunosuppressive effects in vivo and in vitro [48][49] . In several mouse models of acute liver failure, MSCs signi cantly reduce in ammatory cell in ltration, reduce apoptosis, and increase hepatocyte proliferation, thus promoting liver regeneration and improving survival [50][51][52] . MSCs have been reported to modulate adaptive immune responses, induce DC to upregulate the anti-in ammatory cytokine, IL-10, and reduce the secretion of the pro-in ammatory cytokines, TNF-α and IL-12 53 .…”

Section: Disscussionmentioning

confidence: 99%

PPARγ-dependent hepatic macrophage switching acts as a central hub for hUCMSCs-mediated alleviation of decompensated liver cirrhosis in rats

Yuxia

Zhang

Cheng

et al. 2022

Preprint

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Background: Decompensated liver cirrhosis (DLC), a terminal-stage complication of liver disease, is a major cause of morbidity and mortality in patients with hepatopathie. Human umbilical cord mesenchymal stem cell (hUCMSCs) therapy has emerged as a treatment novel alternative for the treatment of DLC. However, optimized therapy protocols and the associated mechanisms are not completely understood. Methods: We constructed a DLC rat model consistent with the typical clinical characteristics combined use of PB and CCL4. By performing dynamic detection of liver morphology and function in rats for 11 weeks, the various disease characteristics of DLC and the therapeutic effect of hUCMSCs on DLC in experimental rats were fully investigated, according to ascites examination, histopathological and related blood biochemical analyses. Flow-cytometry analysis of rat liver, immunofluorescence and RT-qPCR were performed to examine the changes of liver immune microenvironment after hucMSCs treatment. RNA-seq analysis of liver and primary macrophages and hUCMSCs co-culture system in vitro were performed to explore possible signaling pathways. PPARγ antagonist, GW9662, and clodronate liposomes were used to inhibit PPAR activation and pre-exhaustion of macrophages in DLC rats’ liver respectively. Results: We found that changing of the two key issues, the frequency and initial phase of hUCMSCs infusion can affect the efficacy of hUCMSCs and the optimal hUCMSCs treatment schedule is once every week for three weeks at the early-stage of DLC progression, providing the best therapeutic effect in reducing mortality and ascites, and improving liver function in DLC rats. hUCMSCs treatment skewed the macrophage phenotype from M1-type to M2-type through activating PPARγ signaling pathway in liver, which was approved by primary macrophages and hUCMSCs co-culture system in vitro. Both inhibition of PPARγ activation with GW9662 and pre-exhaustion of macrophages in DLC rats’ liver abolished the regulation of hUCMSCs on macrophage polarization, thus attenuating the beneficial effect of hUCMSCs treatment in DLC rats. Conclusions: HUCMSCs treatment on DLC were attributed to the activation of the PPARγ signaling pathway in liver macrophages of DLC rats, which polarizes M1-type macrophages to M2-type, thus inhibiting inflammation and promoting the repair of damaged liver tissue. Our results about different infusion regimens comparison and mechanisms exploration provide a robust theoretical foundation for the future study design of Mesenchymal Stem Cells therapy on DLC.

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Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review

Cited by 33 publications

References 213 publications

3D-ESC-derived MSCs with Enhanced Immunomodulatory Capacity Repair APAP-Induced Liver Injury

3D-ESC-derived MSCs with Enhanced Immunomodulatory Capacity Repair APAP-Induced Liver Injury

Prognostic Scores in Acute Liver Failure Due to Viral Hepatitis

PPARγ-dependent hepatic macrophage switching acts as a central hub for hUCMSCs-mediated alleviation of decompensated liver cirrhosis in rats

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