Liver regeneration enables living donor liver transplantation and is fundamental to repair after liver injury. However, aberrant repair processes, as in the setting of chronic injury due to hepatitis or obesity, can lead to cirrhosis and liver cancer. Considerable research effort, including our own, seeks to clarify fate relationships among cell types involved in liver regeneration, including hepatocytes, cholangiocytes, and stellate cells. However, key knowledge gaps persist regarding mechanisms controlling these cells' plasticity. Further, although an array of signaling pathways have been implicated in liver repair, how these are integrated to specify and maintain progenitor fate within the liver remains unknown. Our ultimate goal is to delineate the mechanisms that control liver regeneration so this knowledge can be applied to prevent and treat key consequences of mis-repair. Our work to date has shown that (1) the Hedgehog (Hh) pathway directs adult liver repair by controlling the size of liver progenitor and myofibroblast (MF) populations; (2) activating the pathway in Hh-responsive cells drives them to become more primitive (i.e., less differentiated, more glycolytic, proliferative, migratory, and fibrogenic), and silencing Hh signaling has the opposite effects; (3) hepatic stellate cells (HSC) are liver-resident members of a network of Hh-responsive perivascular cells (i.e., pericytes) that appear to retain mesenchymal stem cell traits (also reported by others); and (4) in extensive data underpinning our current proposal, Hh signaling interacts with the Hippo/YAP pathway, a distinct developmental pathway known to help control fate decisions in mesenchymal stem cells and to control adult liver growth by regulating liver progenitor population size. However, it is unknown how the Hh-YAP collaboration causes HSC reprogramming or why this is necessary for liver repair. Based on work by us and others, our hypothesis is that Hedgehog activates YAP in HSC to optimize accumulation of MF-HSC that enhance growth of cells with liver repopulating capacity, and this process requires Hh/YAP-dependent reprogramming of HSC through metabolism changes.
Our aims will elucidate the functional consequences of Hh-YAP cross-talk on liver repair and will clarify energy-related mechanisms that coordinate this cross-talk.
Each Aim addresses a key question: How do reprogrammed HSC control hepatocyte plasticity during liver repair? How does Hh reprogram HSC during liver repair? How does Hh interact with YAP to reprogram HSC into proliferative MF? Successful completion of these aims will deepen understanding of mechanisms that co-regulate Hedgehog and YAP/Hippo to achieve effective liver repair. This knowledge will clarify how this intricate process goes awry during human liver disease, and enable development of interventions to enhance appropriate regeneration. Our strong preliminary data and experienced and productive research team position us for success.

Public Health Relevance

Liver regeneration is fundamental to repair after liver injury. It enables living donor liver transplantation but can lead to cirrhosis and liver cancer if not properly regulated. Our work has identified previously-unsuspected mechanisms that control liver regeneration. These discoveries pave the way to optimize repair of injured livers in order to prevent and treat cirrhosis and liver cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Burgess-Beusse, Bonnie L
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Machado, Mariana Verdelho; Diehl, Anna Mae (2018) Hedgehog signalling in liver pathophysiology. J Hepatol 68:550-562
Chen, Kai-Yuan; Shen, Xiling; Diehl, Anna Mae (2018) Prometheus revisited. J Clin Invest 128:2192-2193
Castro, Rui E; Diehl, Anna Mae (2018) Towards a definite mouse model of NAFLD. J Hepatol 69:272-274
Du, Kuo; Hyun, Jeongeun; Premont, Richard T et al. (2018) Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells. Gastroenterology 154:1465-1479.e13
Oh, Seh-Hoon; Swiderska-Syn, Marzena; Jewell, Mark L et al. (2018) Liver regeneration requires Yap1-TGF?-dependent epithelial-mesenchymal transition in hepatocytes. J Hepatol 69:359-367
Verdelho Machado, Mariana; Diehl, Anna Mae (2018) The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol 53:264-278
Chen, Jiamei; Chen, Long; Zern, Mark A et al. (2017) The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 37:1260-1271
Xie, Guanhua; Swiderska-Syn, Marzena; Jewell, Mark L et al. (2017) Loss of pericyte smoothened activity in mice with genetic deficiency of leptin. BMC Cell Biol 18:20
Machado, M V; Michelotti, G A; Jewell, M L et al. (2016) Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis 7:e2096
Swiderska-Syn, Marzena; Xie, Guanhua; Michelotti, Gregory A et al. (2016) Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64:232-44

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