Dr. Anton Titov, MD.: Professor Friedman, what is the hepatic stellate cell? Dr. Anton Titov, MD.: What is its role in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis? NASH. You've done some pioneering work in that regard. Well, 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. And 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. Now, it turns out, we discovered almost or so 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. So 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 they become very busy cells. Stellate cells become very metabolically active. They make a lot of scars, they are contractile, they proliferate. And they lose their vitamin A droplets and become much more like contractile fibroblasts, which are also known as myofibroblasts. And so, that has been the basis of my work, and, I'm pleased to say, 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. And so 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. Dr. Anton Titov, MD.: 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. So 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? Dr. Anton Titov, MD.: What are their hepatic stellate cell-directed therapies for fatty liver disease? That's an important question. :et 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. Dr. Scott Friedman, MD.: 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 kind of 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. And 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. And 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. Dr. Scott Friedman, MD.: But in this case, he's providing an mRNA light 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 and heart. He hasn't studied fibrosis and liver. Dr. Scott Friedman, MD.: 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. And so that 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. So this is a very hot area. It's leveraging not only advanced knowledge about pharmaceutical chemistry and receptor biology but even more advanced banding 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.