Liver regeneration and inflammation: from fundamental science to clinical applications

Campana, Lara; Esser, Hannah; Huch, Meritxell; Forbes, Stuart J.

doi:10.1038/s41580-021-00373-7

Cited by 175 publications

(128 citation statements)

References 242 publications

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“…Macrophages have polarity and are key players in both pro-inflammatory and anti-inflammatory responses [ 24 , 25 ]. LPS, a component of gram-negative bacteria, is known to induce pro-inflammatory effects in macrophages by upregulating the expression levels of Il6 , Mcp1 , Tnfa , and Inos in macrophages isolated from the bone marrow of WT mice.…”

Section: Resultsmentioning

confidence: 99%

“…Usually, harvested quiescent HSCs are activated when cultured on collagen-coated dishes. During this activation, HSCs produce collagen fibers and contribute to the formation of fibrosis [ 24 , 25 ]. To determine whether ONO-1301 directly inhibits HSC activation, mouse HSCs were harvested and seeded on collagen-coated dishes, and after 6 h, ONO-1301 was either added (ONO group) or not (Ctl group).…”

Section: Resultsmentioning

confidence: 99%

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A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

et al. 2022

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Background ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). Methods The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. Results ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. Conclusions The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

et al. 2022

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“…For instance, macrophages hold great promise for regenerative medicine to treat liver disease [105]. The role of inflammation in liver regeneration and the potential clinical applications have been elegantly reviewed elsewhere [106]. The next important challenge is represented by the identification of mesenchymal subpopulations that can be employed in regenerative medicine to stimulate the regenerative potential of epithelial cells and improve the outcome of chronic liver disease.…”

Section: Discussionmentioning

confidence: 99%

The influence of tissue spatial geometry and functional organisation on liver regeneration

Aloia

2022

Seminars in Cell & Developmental Biology

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The adult liver exerts crucial functions, including nutrient metabolism and storage, bile production and drug detoxification. These complex functions expose the liver to constant damage induced by toxins, metabolic intermediates and oxidative stress. However, the adult liver exhibits an exceptional regenerative potential, which allows fast and efficient restoration of tissue architecture and function both after tissue resection and toxic damage. To accomplish its vital role, the liver shows a peculiar tissue architecture into functional units, which follow the gradient of oxygen and nutrients within the parenchyma. Much less is known about the influence of tissue spatial geometry and functional organisation on adult liver regeneration. Here I examine the experimental evidence in mouse models showing that the spatial organisation of the epithelial and mesenchymal compartments plays a key role in liver regeneration and favours the establishment of regenerative adult liver progenitors following liver injury. I also discuss the advantages and limitations of human and mouse 3D hepatic organoid systems, which recapitulate key aspects of liver function and architecture, as models of liver regeneration and disease. Finally, I analyse the role of the YAP/TAZ transcriptional co-activators as a central hub sensing the extracellular matrix (ECM), metabolic and epigenetic remodelling that regulate liver regeneration and promote liver disease, such as fibrosis, chronic liver disease and liver cancer. Together, the findings summarised here demonstrate that local physical and functional cellular interactions determined by the liver peculiar spatial geometry, play a crucial role in liver regeneration, and that their alterations have important implications for human liver disease.

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“…The Forbes group of Edinburgh University reported phase I autologous macrophage therapy and its safety [32]. In addition to macrophages, the regulation of a variety of immune cells, including regulatory T cells, NK cells, and hepatic stellate cells, would be important to induce the activation of this endogenous regenerative ability [33]. Recent technological advances, such as two-photon excitation microscopy and single-cell RNA-Seq, have helped to demonstrate this phenomenon [18].…”

Section: Discussionmentioning

confidence: 99%

Transition of clinical and basic studies on liver cirrhosis treatment using cells to seek the best treatment

et al. 2021

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The liver is a highly regenerative organ; however, its regeneration potential is reduced by chronic inflammation with fibrosis accumulation, leading to cirrhosis. With an aim to tackle liver cirrhosis, a life-threatening disease, trials of autologous bone marrow cell infusion (ABMi) therapy started in 2003. Clinical studies revealed that ABMi attenuated liver fibrosis and improved liver function in some patients; however, this therapy has some limitations such as the need of general anesthesia. Following ABMi therapy, studies have focused on specific cells such as mesenchymal stromal cells (MSCs) from a variety of tissues such as bone marrow, adipose tissue, and umbilical cord tissues. Particularly, studies have focused on gaining mechanistic insights into MSC distribution and effects on immune cells, especially macrophages. Several basic studies have reported the use of MSCs for liver cirrhosis models, while a number of clinical studies have used autologous and allogeneic MSCs; however, there are only a few reports on the obvious substantial effect of MSCs in clinical studies. Since then, studies have analyzed and identified the important signals or components in MSCs that regulate immune cells, such as macrophages, under cirrhotic conditions and have revealed that MSC-derived exosomes are key regulators. Researchers are still seeking the best approach and filling the gap between basic and clinical studies to treat liver cirrhosis. This paper highlights the timeline of basic and clinical studies analyzing ABMi and MSC therapies for cirrhosis and the scope for future studies and therapy.

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Liver regeneration and inflammation: from fundamental science to clinical applications

Cited by 175 publications

References 242 publications

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

The influence of tissue spatial geometry and functional organisation on liver regeneration

Transition of clinical and basic studies on liver cirrhosis treatment using cells to seek the best treatment

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