Hepatic Stellate Cells: Key Drivers of Fatty Liver Disease and Fibrosis

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• Stellate Cell Biology and Function
• Cell Activation Process in Liver Disease
• NASH Pathophysiology Components
• Current Stellate Cell-Targeted Therapies
• CAR-T Cell Therapy for Fibrosis
• mRNA Lipid Nanoparticle Technology
• Future Directions in Fibrosis Treatment
• Full Transcript

Stellate Cell Biology and Function

Dr. Scott Friedman, MD, describes hepatic stellate cells as resident liver cells that function as liver-specific pericytes. These specialized cells wrap around blood vessels in the liver sinusoids. In their normal state, hepatic stellate cells remain relatively quiescent and non-proliferative. Dr. Scott Friedman, MD, emphasizes their crucial role in storing vitamin A (retinoids), which represents one of their most important physiological functions.

Dr. Scott Friedman, MD, developed pioneering methods to isolate stellate cells from both rodent and human liver tissue. This breakthrough enabled researchers to study these cells in culture and replicate their responses observed in living organisms. The isolation techniques established by Dr. Friedman have become fundamental to liver fibrosis research worldwide.

Cell Activation Process in Liver Disease

Hepatic stellate cells undergo dramatic transformation when the liver experiences injury. Dr. Scott Friedman, MD, explains that these cells activate and become metabolically highly active. Activated stellate cells lose their characteristic vitamin A droplets and transform into contractile fibroblasts known as myofibroblasts.

Dr. Scott Friedman, MD, notes that activated stellate cells proliferate extensively and produce excessive scar tissue. This fibrogenic activity drives the progression of liver fibrosis and ultimately cirrhosis. Understanding this activation process has become the focus of numerous research laboratories and pharmaceutical companies seeking to develop anti-fibrotic therapies.

NASH Pathophysiology Components

Non-alcoholic steatohepatitis (NASH) comprises three key pathological components. Dr. Scott Friedman, MD, clarifies that NASH involves liver fat accumulation (steatosis), inflammation, and liver scarring (fibrosis). This triad of features distinguishes NASH from simple fatty liver disease (NAFLD).

Dr. Scott Friedman, MD, emphasizes that therapeutic approaches for NASH must address all three components. While reducing scar formation is crucial, treatments must also attenuate the underlying injury that drives stellate cell activation. This comprehensive understanding guides current drug development strategies for NASH treatment.

Current Stellate Cell-Targeted Therapies

Several therapeutic approaches specifically target hepatic stellate cells to combat fibrosis. Dr. Scott Friedman, MD, describes drugs that block receptors on stellate cell surfaces, including integrin inhibitors and tyrosine kinase receptor blockers. These medications aim to interrupt signaling pathways that promote stellate cell activation.

Additional therapeutic targets include molecules like transforming growth factor-beta (TGF-β) and connective tissue growth factor-beta. Dr. Scott Friedman, MD, explains that blocking these profibrotic pathways can potentially turn off the scar-producing machinery of activated stellate cells. Pharmaceutical companies are actively developing compounds that target these specific pathways.

CAR-T Cell Therapy for Fibrosis

Revolutionary approaches using CAR-T cells represent a futuristic direction in fibrosis treatment. Dr. Scott Friedman, MD, discusses work from Dr. Scott Lowe and Dr. Michel Sadelain who developed specialized chimeric antigen receptor T-cells. These engineered lymphocytes specifically attack the most fibrogenic subpopulation of activated stellate cells.

Dr. Scott Friedman, MD, notes that CAR-T cells directed against activated stellate cells can clear these pathological cells and improve fibrosis. This cell-based therapy approach offers a targeted method to eliminate the "worst actors" in fibrosis progression without affecting healthy tissue. The technology represents a significant advancement in precision medicine for liver disease.

mRNA Lipid Nanoparticle Technology

Groundbreaking research using mRNA lipid nanoparticles has opened new possibilities for fibrosis treatment. Dr. Scott Friedman, MD, highlights spectacular work from Dr. Jonathan Epstein's laboratory at the University of Pennsylvania. Their approach uses lipid nanoparticles to deliver mRNA that reprogrammes normal T-cells within the body into fibrosis-fighting CAR-T cells.

Dr. Scott Friedman, MD, explains that this technology leverages the same platform used in Moderna and Pfizer COVID-19 vaccines. The mRNA lipid nanoparticles can program lymphocytes to specifically target and eliminate fibrogenic cells in damaged tissues. This approach has demonstrated success in cardiac fibrosis models and holds promise for liver applications.

Future Directions in Fibrosis Treatment

The field of anti-fibrotic therapy is rapidly evolving with multiple innovative approaches. Dr. Scott Friedman, MD, emphasizes that current research combines advanced pharmaceutical chemistry, receptor biology, and cutting-edge delivery technologies. The convergence of these disciplines is accelerating the development of effective treatments for liver fibrosis.

Dr. Friedman encourages researchers and clinicians to examine recent publications in this field, particularly the work published in Science by Dr. Rurik and colleagues. These studies provide detailed diagrams and descriptions that help communicate the novelty and excitement surrounding emerging anti-fibrotic technologies. The future of fibrosis treatment appears increasingly promising as these advanced therapies move toward clinical application.

Full Transcript

Dr. Anton Titov, MD: Professor Friedman, what is the hepatic stellate cell? What is its role in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis? You've done some pioneering work in that regard.

Dr. Scott Friedman, MD: Thank you for asking, because that's been my passion for almost 40 years now. The hepatic stellate cell is a resident cell that's in the normal liver. It is a very interesting cell because it is what's called a liver-specific pericyte. It wraps itself around the blood vessels in the liver. Those blood-vessel units are known as sinusoids.

In normal liver, the stellate cell is relatively quiescent and non-proliferative. One of the most important functions of a normal stellate cell is to store vitamin A or retinoids. We discovered that one could isolate those stellate cells originally from mouse and then from human liver. We could replicate their response in vivo when we grew stellate cells in culture.

We developed, for the first time, a method to isolate stellate cells from rodents, and then from human liver. We showed that when stellate cells become injured, or in the setting of injury, they activate and become very busy cells. Stellate cells become very metabolically active. They make a lot of scars, they are contractile, they proliferate.

They lose their vitamin A droplets and become much more like contractile fibroblasts, which are also known as myofibroblasts. That has been the basis of my work, and work of many laboratories around the world over the past few decades. Because we know that if we can harness an understanding of how stellate cells make a scar, perhaps we can interfere with their function as a fibrogenic or scar-making cell.

There's a lot of effort, both in my laboratory, in many others, and also in a lot of companies, to understand how stellate cells become fibrogenic and how to block their ability to make the scar that leads to fibrosis and cirrhosis. So it's a very interesting cell type. It still remains of great interest to the field.

It continues to yield amazing mysteries about what stellate liver cell does, how it behaves, how it is regulated, and ultimately, how we can attenuate its activity to prevent scar formation.

Dr. Anton Titov, MD: Considering this huge importance of hepatic stellate cells, are there specific therapies that target those cells? Or some of their metabolism, perhaps the environment around them? What are their hepatic stellate cell-directed therapies for fatty liver disease?

Dr. Scott Friedman, MD: That's an important question. Let me just step back for a minute and remind our viewers that NASH is comprised of liver fat, inflammation, and then liver scarring. So approaches to treating NASH with new drugs aren't just focused on the scarring. Therapy is also focused on attenuating the injury that is driving the scarring.

But in addition, there are drugs that are specifically attacking the stellate cells in hopes of turning off their scar machinery. Among those drugs are molecules that block receptors on the cell surface, for example, integrins, so-called tyrosine kinase receptors, as well as molecules like TGF or transforming growth factor-beta, connective tissue growth factor-beta.

There are a number of molecules and receptors that are on the surface or expressed in the milieu that drive the activation of stellate cells. And so there's a concerted effort to block those pathways that make the cells fibrogenic.

It is a more revolutionary and futuristic approach that my lab was participating in that came from the laboratory of Dr. Scott Lowe and Dr. Michel Sadelain, where they develop a very specialized kind of attacking lymphocyte known as a CAR-T cell, which stands for chimeric antigen receptor. They generated special specific CAR-T cells that would attack a subset of the stellate cells that are the most fibrogenic, the worst actors in driving fibrosis.

They showed that if you give CAR-T cells directed at the most activated stellate cells, you can clear those cells and improve fibrosis. So that's a kind of futuristic cell-based therapy.

Even more recently, spectacular work from the laboratory of Dr. Jonathan Epstein at the University of Pennsylvania built on the approach that he had also pioneered using CAR-T cells. But in this case, he's providing an mRNA lipid nanoparticle to turn normal T-cells within the body into CAR-T cells that will then attack fibrosis-causing cells.

Now in his case, he studies fibrosis in heart. He hasn't studied fibrosis in liver. But if the idea of lipid nanoparticles and mRNA sounds familiar, it's because that's the basis of at least the Moderna and Pfizer COVID-19 vaccines.

Those miraculous success stories have brought lipid nanoparticle and mRNA therapies right into the spotlight, into the mainstream therapies not only as vaccines but also as therapies that could program lymphocytes to clear fibrogenic cells in damaged tissues, whether it's heart, liver, or possibly other tissues as well.

This is a very hot area. It's leveraging not only advanced knowledge about pharmaceutical chemistry and receptor biology but even more advanced blending of lipid nanoparticles, mRNA technology and the possibility of programming T cells to kill fibrosis-causing cells.

Dr. Epstein's work was published in Science in the last couple of months. The first author is Dr. Rurik and colleagues. I encourage your viewers to take a look at that. They have some lovely diagrams and descriptions that help simplify the message but still underscore the novelty and the excitement around this technology.