Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles

Watanabe, Takayuki; Tsuchiya, Atsunori; Takeuchi, Suguru; Nojiri, Shunsuke; Yoshida, Tomoaki; Ogawa, Masahiro; Ichii, Michiko; Takamura, Masaaki; Suganami, Takayoshi; Ogawa, Yoshihiro; Terai, Shuji

doi:10.1016/j.reth.2020.03.012

Cited by 57 publications

(74 citation statements)

References 25 publications

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“…MSC ameliorated oxidative stress, inflammation, and tissue damage, corroborating our previous results showing regression of fibrosis and cell death as well as attenuation of inflammatory pathways [ 20 ], consistent with findings demonstrating resolution of inflammation, fibrosis, and lipid load in rodent models of NASH [ 90 , 91 ]. The mechanisms behind, however, remain elusive.…”

Section: Discussionsupporting

confidence: 90%

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

et al. 2020

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Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury.

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Section: Discussionsupporting

confidence: 90%

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

et al. 2020

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“…These ADSC EVs anti-fibrosis effects were replicated again in a mice model of NASH, in which the NASH mice with ADSC-EVs treatment had better liver improvements and greater anti-inflammatory macrophages [95]. However, no effect was observed in the lipid accumulation [95]. Similar anti-fibrosis effects on HSCs are shown in the other studies of EVs isolated from induced pluripotent stem cells (iPSC) [96], amnion-derived MSCs (AMSCs) [97], human liver stem cells (HLSCs) [98], and human umbilical cord-derived MSCs [99].…”

Section: Evs From the Mesenchymal Stem Cells As A Treatment Optionmentioning

confidence: 79%

“…Similarly, the ADSC EVs with a high level of miR-122 expression suppressed the activation and proliferation of HSCs via the reduction of insulin-like growth factor receptor 1 (IGF1R), Cyclin G(1) (CCNG1), and prolyl-4-hydroxylase α1 (P4HA1) gene expressions [94]. These ADSC EVs anti-fibrosis effects were replicated again in a mice model of NASH, in which the NASH mice with ADSC-EVs treatment had better liver improvements and greater anti-inflammatory macrophages [95]. However, no effect was observed in the lipid accumulation [95].…”

Section: Evs From the Mesenchymal Stem Cells As A Treatment Optionmentioning

confidence: 88%

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver damage disease from a simple fatty liver (steatosis) to more severe liver conditions such as non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Extracellular vesicles (EVs) are a heterogeneous group of small membrane vesicles released by various cells in normal or diseased conditions. The EVs carry bioactive components in their cargos and can mediate the metabolic changes in recipient cells. In the context of NAFLD, EVs derived from adipocytes are implicated in the development of whole-body insulin resistance (IR), the hepatic IR, and fatty liver (steatosis). Excessive fatty acid accumulation is toxic to the hepatocytes, and this lipotoxicity can induce the release of EVs (hepatocyte-EVs), which can mediate the progression of fibrosis via the activation of nearby macrophages and hepatic stellate cells (HSCs). In this review, we summarized the recent findings of adipocyte- and hepatocyte-EVs on NAFLD disease development and progression. We also discussed previous studies on mesenchymal stem cell (MSC) EVs that have garnered attention due to their effects on preventing liver fibrosis and increasing liver regeneration and proliferation.

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“…57 Since recent studies suggest that MSC-conditioned medium (or exosomes present therein) are as effective as MSCs themselves, soluble factors are currently of great interest regarding their regenerative potential in the therapy of cirrho-sis. 7,[34][35][36][57][58][59][60] Via soluble factors, MSCs may have therapeutic effects in cirrhosis even if they do not infiltrate the injured liver. Our group was the first to demonstrate in real time (using two-photon excitation microscopy) that peripheral intravenous administration of DsRed-labeled MSCs in a murine cirrhosis model resulted in the majority of MSCs being retained within the pulmonary vasculature, while only a few reached the liver.…”

Section: Cell-based Therapy: Characteristics Of Mscs and Macrophagesmentioning

confidence: 99%

“…By such mechanisms, MSCs are able to remotely influence the activities of many cellular effectors [ 57 ]. Since recent studies suggest that MSC-conditioned medium (or exosomes present therein) are as effective as MSCs themselves, soluble factors are currently of great interest regarding their regenerative potential in the therapy of cirrhosis [ 7 , 34 - 36 , 57 - 60 ].…”

Section: Cell-based Therapy: Characteristics Of Mscs and Macrophagesmentioning

confidence: 99%

The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future

2021

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Cirrhosis is a chronic condition that can lead to liver failure. Currently, the viable option for decreasing mortality is liver transplantation. However, transplant surgery is highly invasive. Therefore, cell-based therapy has been developed as an alternative. Based on promising findings from preclinical research, some new trials have been registered. One of them was autologous bone marrow cell infusion therapy and found that ameliorating liver fibrosis activated liver regeneration. Now, majority of trials focus on low-immunogenicity mesenchymal stem cells (MSCs) appropriate for allogeneic administration. However, despite about 20 years of research, only a limited number of cell-based therapies have entered routine practice. Furthermore, potential shortcomings of cell-based therapy include a limit on the number of cells, which may be administered, as well as their failure to infiltrate target organs. On the other hand, these research show that MSCs act as “conducting cells” and regulate host cells including macrophages via extracellular vesicles (EVs) or exosome signals, leading to ameliorate liver fibrosis and promote regeneration. Therefore, the concept of cell-free therapy, which makes use of cell-derived EVs or exosomes, is attracting attention. Cell-free therapies may be safely administered in large doses and are able to infiltrate target organs. However, development of cell-free therapy exhibits its own set of challenges and such therapy may not be completely curative in the context of liver disease. This review describes the history of cell-based therapy research and recent advances in cell-free therapy, as well as discussing the need for more effective therapies.

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Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles

Cited by 57 publications

References 25 publications

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future

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