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Journal Club August 21st 2018 13:00 ET / 18:00 UK

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For the August edition of the Journal club, we will be taking a look at this new paper which focuses on boosting liver regeneration by inhibition of TGFβ1. We will be streaming the Journal Club live from our Facebook page.

Setting liver regeneration free

The liver is an excellent model of organ regeneration; however, regeneration may fail in a normal liver after acute severe injury such as acetaminophen poisoning. Bird and colleagues now show that a process that prevents proliferation termed senescence, which is classically associated with aging and carcinogenesis, inhibits the liver’s regenerative cells after acute injury. This senescence can be spread from cell to cell by the signaling molecule transforming growth factor–β (TGFβ). When TGFβ signaling was blocked during acetaminophen poisoning in mice, senescence was impeded, regeneration accelerated, and mouse survival increased. Therefore, targeting senescence induced by acute tissue injury is an attractive therapeutic approach to improve regeneration.

Abstract

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor–β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

CategoryJournal club
About the author
Oliver Medvedik

Oliver Medvedik

Oliver Medvedik, Co-founder of Genspace citizen science laboratory in Brooklyn NY, earned his Ph.D. at Harvard Medical School in the Biomedical and Biological Sciences program. As part of his doctoral work he has used single-celled budding yeast as a model system to map the genetic pathways that underlie the processes of aging in more complex organisms, such as humans. Prior to arriving in Boston for his doctoral studies, he has lived most of his life in New York City. He obtained his bachelor’s degree in biology from Hunter College, City University of New York. Since graduating from Harvard, he has worked as a biotechnology consultant, taught molecular biology to numerous undergraduates at Harvard University and mentored two of Harvard’s teams for the international genetically engineered machines competition (IGEM) held annually at M.I.T. Oliver is also the Director of The Maurice Kanbar Center for Biomedical Engineering at the Cooper Union, New York City. The Maurice Kanbar Center for Biomedical Engineering is open to all Cooper Union faculty and students working on bioengineering projects requiring equipment and space for tissue culture, genetic engineering, biomechanics, and related research. Faculty that is currently using the facility are pursuing groundbreaking biomedical research in such fields as biomedical devices, tissue engineering, obstructive sleep apnea biomechanics also collaborating with several major New York City-based hospitals. The Kanbar Center continues to provide space for undergraduate teams participating in the international genetically engineered competition (iGEM) during the summer, as well as space for courses that offer a biological laboratory component.
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