How a liver-on-a-chip model of fatty liver disease could assist in preventing a global healthcare crisis

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Obesity has become a global epidemic. About one-third of the adult population in the United States is now obese. Internationally, the frequency of obesity has almost tripled since the 1970s. This surge has led to a rise in serious health conditions, particularly cardiovascular disease, type-two diabetes, and cancers.

Another health concern on the rise, associated with obesity, is Metabolic-Dysfunction  Associated Steatotic Liver Disease, or MASLD, previously known as Non-Alcoholic Fatty Liver Disease (NAFLD).

The initial stage of MASLD, a fatty liver, is comparatively reversible and harmless; however, it can advance to Metabolic-Dysfunction Associated Steatohepatitis (MASH), previously known as Non-Alcoholic Steatohepatitis (NASH) where the liver undergoes inflammation and fibrosis.

The presence of chronic inflammation can result in cirrhosis, a severe and irreversible condition characterized by the replacement of functional liver cells with scar tissue. 

MASH is already one of the foremost reasons for liver transplantation in the USA. However, projections indicate that it will soon surpass hepatitis as the principal cause, creating a substantial economic problem.

Research and development efforts have focused on creating anti-MASH therapeutics in response to this issue. Despite these efforts, only one drug candidate has successfully made it through human trials and gained approval.

This begs the question: How can we enhance our understanding of this disease? How can we create more accurate models of the human disease? How can we improve predictions of human responses?

Dr. Michele Vacca, a Clinical Research Associate (then) at the University of Cambridge, published a study addressing these questions with a “sum is greater than the parts” approach to unravel the intricate, overlapping, and multi-faceted inflammatory pathways associated with liver fibrosis.

The aim is to identify crucial, potentially “druggable” elements in MASH. To develop druggable targets for the treatment of fatty liver disease, it is essential to gain a comprehensive understanding of the role played by inflammation in the development of MASLD to MASH and cirrhosis.

Dr. Vacca’s research concentrates on the TGFß pathway, a significant signaling pathway involved in the development of liver fibrosis. TGFß introduces complexity as specific ligands can activate canonical and non-canonical branches of the signaling cascade.

An example of such a ligand is Bone morphogenic protein 8B (BMP8B), which is nearly absent in a normal human liver but sees increased expression with MASLD disease progression. This led Dr. Vacca to ask the question: what is the role of BMP8B in MASH?

Various traditional methods, including 2D cell culture and animal models of MASH, were employed to answer this question. However, when it comes to physiological relevance, each approach has its restrictions.

For instance, while 2D cell culture models are simple, cost-effective, and convenient, they lack “real-life” complexity. Primary hepatocytes cultured in 2D lose their identity quickly, resembling cancer cells more than normal cells.

To address these shortcomings, animal models are used to confirm findings. However, inter-species differences can yield results that may not be directly translatable to humans.

To solve these challenges, Dr. Vacca sought a complementary solution to fill knowledge gaps and validate discoveries, leading him to CN Bio’s in vitro human-relevant NASH disease model.

Using CN Bio’s Liver-on-a-Chip approach, also known as a Liver Microphysiological System, primary human hepatocytes can be cultured for up to four weeks under constant perfusion without losing their identity.

Various additional human cell types, including Kupffer, and stellate cells can be co-cultured to form 3D liver microtissues that more precisely replicate the human liver and its microarchitecture. 

By exposing the model to fatty acids, a disease state resembling human MASH is induced with high accuracy, offering an appropriate system to study signaling pathways such as the TGFß/BMP pathway.

The human-relevant results obtained using this exclusive Liver-on-a-Chip model assisted Dr. Vacca in confirming previous findings, delivering new insights, and integrating data from traditional methods to achieve a more comprehensive understanding of the disease.

The research conclusions show that BMP8B, a secreted peptide absent in normal liver, is upregulated in MASH hepatocytes and stellate cells and that it modulates TGFß BMP signaling.

While BMP8B coordinates the liver’s wound-healing response, it promotes inflammation and fibrosis in MASH. BMP8B is both secreted and disease-specific, making it a promising druggable target for anti-MASH therapeutics.

About CN Bio

CN Bio develops human organ-on-chip technologies: devices that enable the formation of miniature models of human organs in the lab. We provide products and services to the pharmaceutical industry and in the past 3 years have used our proprietary organ-on-chip models in drug discovery and drug safety programs with more than 25 pharmaceutical companies. CN Bio has also pursued research to develop disease organ-on-chip models with successful programmes resulting in novel models of non-alcoholic steatohepatitis and Hepatitis B virus infection.

Working closely with academic pioneers in the bio-engineering field, and pharmaceutical and industrial partners, CN Bio continues to advance next-generation human Organs-on-Chips.


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