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Q & A with Tatiana Kisseleva

tatiana-kisseleva.jpegDr. Tatiana Kisseleva, a research scientist and expert in liver fibrosis, planned to be a liver surgeon before launching a career dedicated to full-time research. Since joining UC San Diego in 2007, her lab has focused on the characterization of the origin of fibrogenic myofibroblasts and identification of novel targets for anti-fibrotic therapy. In this interview, Dr. Kisseleva shares the journey that took her from Moscow to Germany, New York, and finally San Diego; discusses how her work on liver fibrosis extends to other surgical fields; and offers a taste of how scientific insights gleaned from her lab are translating into clinical practice.

October 5, 2018 | Interview by Lindsay Morgan

You are best known as a scientist and expert in liver fibrosis, but you originally wanted to be a surgeon . What drew you to surgery initially?

I’m the 4th generation of physicians in my family. My great-grandmother was a physician, my grandmother was an obstetrician, and my father was a pediatric orthopedic surgeon. I worked in the operating room all seven years during medical school at the hospital affiliated with the Russian University of Friendship in Moscow.

You received your PhD at the Institute of Biochemistry in Germany at Christian-Albrecht University, and eventually went on to Columbia University, where you trained in biochemistry, transgenic technology and signal transduction. What prompted your move from clinical surgery towards full-time research?

I started scientific work my second year of medical school, and my mentor in surgery was very oriented towards science. Once I finished medical school, I knew I wanted to be a scientist. It’s probably one of the few occupations where your curiosity drives your motivation. You have a theory, you test it, and sometimes the result is completely not what you thought it would be. But maybe you come to something novel. And that’s a really the bright moment.

How does your surgical training make you a different kind of scientist?

I always say I can professionally operate on a mouse. But really, medical school and surgical training gives you another perspective on life and provides a link between research and translational medicine.

You joined UC San Diego in 2007 and have led and participated in a number of exciting research collaborations. What is your lab currently working on?

We have several projects on nonalcoholic steatohepatitis (NASH) and alcohol induced hepatocellular carcinoma, and liver fibrosis. Our main focus is the study of the origin of myofibroblasts, and their role in the development of fibrosis, and finding new targets for therapy.

We have a study exploring the role of Interleukin 17 (IL-17) in fibrosis and cancer. We’ve shown that IL-17 is critical for development of liver fibrosis, and inhibition of IL-17 signaling can attenuate development of experimental liver fibrosis by 75%.

We’ve also looked at inactivation of myofibroblasts as a mechanism of liver fibrosis resolution. Regression of liver fibrosis is associated with disappearance of fibrogenic myofibroblasts. For many years people thought you needed to induce apoptosis of activated hepatic myofibroblasts in fibrotic liver, but we demonstrated that during regression of liver fibrosis, activated hepatic stellate cells / myofibroblasts can also inactivate, e.g. stop producing Collagen Type I, re-express quiescent markers, and revert into a quiescent-like state. Inactivation of myofibroblasts might become a novel target for anti-fibrotic therapy.

And we have a project that looks at the role of Portal Fibroblasts in cholestatic liver disease, which is related to the obstruction of bile ducts. Myofibroblasts arise from a different source in response to bile duct obstruction, and phenotypically differ from Hepatic Stellate Cells. We have recently identified a novel mechanism of Portal Fibroblast activation in mice and humans. Specifically, two antigens, Mesothelin and CA125, known to be upregulated in ovarian and pancreatic cancer, critically regulate proliferation and fibrogenic activation of Portal Fibroblasts. This mechanism is novel, and has not been previously described

Non-alcoholic liver disease (NASH) will probably become the predominant liver disease which require liver transplantation. Here at UCSD, we collaborate with Drs. David Brenner, Michael Karin, Jerry Olefsky, Rohit Loomba, Dan Kaufman, Sylvia Evans, Chris Benner, and Sven Heinz, Ludmil Alexandrov, and Chris Glass to study the pathogenesis of this particular disease from different perspectives, including different molecular mechanisms.

Your lab is unique in that you are able to work with human cells, which is pretty incredible.

Yes, we have a program with Lifesharing wherein livers that are rejected for transplantation for various reasons can be used for research. We just opened a new lab at UC San Diego where we are isolating different cell types from human livers: hepatocytes, stellate cells, macrophages cells, and endothelial cells. These livers are perfused with protective solutions and the cells stay viable for a longer time, which ensures high quality of isolated cells. This allows us to test in human cells our original findings in mice, such as new pathways or targets associated with resolution of liver fibrosis or inactivation of collagen-producing myofibroblasts. This is an important part of translational research, which links preclinical studies to clinical applications. We are very fortunate to have this program. And my affiliation with the Department of Surgery made it possible to develop this human aspect of our research.

As you look at how experimental models have helped you better understand the mechanisms that underlie fibrosis, in the liver particularly, have you been able to see these insights translated into clinical practice?

We think that several of our publications can be taken to clinical practice. Especially for cholestatic fibrosis, we’ve identified a new pathway which activates fibroblasts in livers injured by cholestasis, and blocking of Mesothelin might be beneficial for suppression of activation and proliferation of Portal Fibroblasts in the injured liver.

Your laboratory work is generally thought of as impacting the field of transplantation but tissue repair and regeneration is really a central focus area for all surgery research. How do you see the work on fibrosis translating beyond liver into other surgical fields where scarring and fibrosis are also problems?

That’s a great question. We actually did not stop on the liver. For example, we have a surgeon from Kyoto University in Japan, who is doing a post-doctoral fellow ship in our lab looking at how the mechanism responsible for cholestatic fibrosis may also apply to fibrosis of the lungs, kidneys and pancreas.

What are you most excited about for the future?

I think about the new developments in science that are happening now. For example, we can now treat HCV and melanoma. This is a very exciting time, because I believe that in the next 10 to 20 years we will solve other problems that will help people live longer and be healthier.

What advice would you give to surgical trainees who want to blend a surgical and research career?

I would highly advise surgical trainees to take advantage of the option to rotate through different research labs. It broadens your perspective. Engagement of surgeon-scientists in research will help to bring new discoveries into clinical practice.