Molecular Mechanisms of Endogenenous Liver Regeneration

Objectives

Our long-term goal is to identify new and innovative strategies to improve liver regeneration following acute and chronic injury 

Our 5-year goal is to characterize the immune cells and to identify their inflammatory mediators (cytokines and chemokines), which induce and stimulate proliferation of hepatocytes and hepatic progenitor cells. Additionally, we aim to determine whether these factors have opposing effects on hepatocytes and progenitor cells, which might explain the regulatory mechanisms that transfer regeneration from one compartment to the other. 

Research Focus

The liver has the remarkable ability to regenerate itself. It is well established that there are two forms of liver regeneration, one mediated by proliferation of hepatocytes. Partial hepatectomy (PH) is a well-established method to study liver regeneration of mature, normally quiescent hepatocytes in rodents. Similarly, carbon tetrachloride (CCl4) intoxication, is an experimental model believed to trigger hepatocyte regeneration only by self duplication of hepatocytes. If hepatocytes are inhibited from proliferation or if they are senescent, liver repair is undertaken by hepatic progenitor cells/ oval cells, which proliferate, migrate and differentiate into hepatocytes and cholangiocytes. These cells are characterized by expression of fetal hepatocyte (CK8, Albumin), cholangiocyte (A6, CK19) and hematopoetic (CD34, Sca, CD45) markers. In patients with chronic liver diseases, the presence of progenitor cells correlates with the degree of injury and inflammation. Additionally, progenitor cell proliferation has also been observed in patients with acute liver failure and their appearance appears to correlate positively with clinical outcome. In rodents, a strong oval cell response can be activated with a choline-deficient, ethionine supplemented diet (CDE diet), which induces a severe steatohepatitis within one week or by feeding mice with the toxin 3,5-diethoxy- carbonyl-1,4-dihydrocollidine (DDC). The liver is enriched in macrophages, NK cells, NKT cells, and CD4+ and CD8+ cells encompassing 25% of all cells. The coresidence of these lymphocytes in the liver creates a unique environment capable of regulating liver homeostasis. Experimental studies with rodents suggest that T- and NK-cells are not only required to eliminate pathogenic microorganisms, but that they also regulate liver regeneration by supporting proliferation of hepatocytes and hepatic progenitor cells under noninfectious conditions suggesting a crosstalk between the regenerating liver and the immune system. 

Collaborations

Publications

2013 - ongoing

2016

Ritorto MS, Rhode H, Vogel A, Borlak J. Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC. Biol Chem. 2016;397(11):1147-62.

Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schutt J, Limbourg F, Konecke C, Schreder A, Michael A, Misslitz AC, Healy ME, Geffers R, Clavel T, Haller D, Unger K, Finegold M, Weber A, Manns MP, Longerich T, Heikenwalder M, Vogel A. Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development. Cancer Cell. 2016;30(2):308-23.

2015

Orlik J, Schungel S, Buitrago-Molina LE, Marhenke S, Geffers R, Endig J, Lobschat K, Rossler S, Goeppert B, Manns MP, Gross A, Vogel A. The BH3-only protein BID impairs the p38-mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice. Hepatology. 2015;62(3):816-28.

Feng T, Dzieran J, Gu X, Marhenke S, Vogel A, Machida K, Weiss TS, Ruemmele P, Kollmar O, Hoffmann P, Grasser F, Allgayer H, Fabian J, Weng HL, Teufel A, Maass T, Meyer C, Lehmann U, Zhu C, Mertens PR, Gao CF, Dooley S, Meindl-Beinker NM. Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma. Clin Sci (Lond). 2015;128(11):761-74.

>De Ponti A, Wiechert L, Schneller D, Pusterla T, Longerich T, Hogg N, Vogel A, Schirmacher P, Hess J, Angel P. A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma. Cancer Lett. 2015;369(2):396-404.

Orlik J, Schungel S, Buitrago-Molina LE, Marhenke S, Geffers R, Endig J, Lobschat K, Rossler S, Goeppert B, Manns MP, Gross A, Vogel A. The Bh3-Only Protein Bid Impairs the P38-Mediated Stress Response and Promotes Hepatocarcinogenesis During Chronic Liver Injury in Mice. Hepatology. 2015;62(3):816-28.

Mobus S, Yang D, Yuan Q, Ludtke TH, Balakrishnan A, Sgodda M, Rani B, Kispert A, Arauzo-Bravo MJ, Vogel A, Manns MP, Ott M, Cantz T, Sharma AD. Microrna-199a-5p Inhibition Enhances the Liver Repopulation Ability of Human Embryonic Stem Cell-Derived Hepatic Cells. J Hepatol. 2015;62(1):101-10.

Kirstein MM, Metzler F, Geiger E, Heinrich E, Hallensleben M, Manns MP, Vogel A. Prediction of Short- and Long-Term Outcome in Patients with Autoimmune Hepatitis. Hepatology. 2015;62(5):1524-35.

Feng T, Dzieran J, Gu X, Marhenke S, Vogel A, Machida K, Weiss TS, Ruemmele P, Kollmar O, Hoffmann P, Grasser F, Allgayer H, Fabian J, Weng HL, Teufel A, Maass T, Meyer C, Lehmann U, Zhu C, Mertens PR, Gao CF, Dooley S, Meindl-Beinker NM. Smad7 Regulates Compensatory Hepatocyte Proliferation in Damaged Mouse Liver and Positively Relates to Better Clinical Outcome in Human Hepatocellular Carcinoma. Clin Sci (Lond). 2015;128(11):761-74.

De Ponti A, Wiechert L, Stojanovic A, Longerich T, Marhenke S, Hogg N, Vogel A, Cerwenka A, Schirmacher P, Hess J, Angel P. Chronic Liver Inflammation and Hepatocellular Carcinogenesis Are Independent of S100a9. Int J Cancer. 2015;136(10):2458-63.

2014

Marhenke S, Buitrago-Molina LE, Endig J, Orlik J, Schweitzer N, Klett S, Longerich T, Geffers R, Sanchez Munoz A, Dorrell C, Katz SF, Lechel A, Weng H, Krech T, Lehmann U, Dooley S, Rudolph KL, Manns MP, Vogel A. P21 Promotes Sustained Liver Regeneration and Hepatocarcinogenesis in Chronic Cholestatic Liver Injury. Gut. 2014;63(9):1501-12.

2013

Yuan Q, Loya K, Rani B, Mobus S, Balakrishnan A, Lamle J, Cathomen T, Vogel A, Manns MP, Ott M, Cantz T, Sharma AD. Microrna-221 Overexpression Accelerates Hepatocyte Proliferation During Liver Regeneration. Hepatology. 2013;57(1):299-310.

Wuestefeld T, Pesic M, Rudalska R, Dauch D, Longerich T, Kang TW, Yevsa T, Heinzmann F, Hoenicke L, Hohmeyer A, Potapova A, Rittelmeier I, Jarek M, Geffers R, Scharfe M, Klawonn F, Schirmacher P, Malek NP, Ott M, Nordheim A, Vogel A, Manns MP, Zender L. A Direct in Vivo Rnai Screen Identifies Mkk4 as a Key Regulator of Liver Regeneration. Cell. 2013;153(2):389-401.

Schrem H, Kurok M, Kaltenborn A, Vogel A, Walter U, Zachau L, Manns MP, Klempnauer J, Kleine M. Incidence and Long-Term Risk of De Novo Malignancies after Liver Transplantation with Implications for Prevention and Detection. Liver Transpl. 2013;19(11):1252-61.

Pusterla T, Nemeth J, Stein I, Wiechert L, Knigin D, Marhenke S, Longerich T, Kumar V, Arnold B, Vogel A, Bierhaus A, Pikarsky E, Hess J, Angel P. Receptor for Advanced Glycation Endproducts (Rage) Is a Key Regulator of Oval Cell Activation and Inflammation-Associated Liver Carcinogenesis in Mice. Hepatology. 2013;58(1):363-73. Epub 2013/03/19.

Kirstein MM, Boukouris AE, Pothiraju D, Buitrago-Molina LE, Marhenke S, Schutt J, Orlik J, Kuhnel F, Hegermann J, Manns MP, Vogel A. Activity of the Mtor Inhibitor Rad001, the Dual Mtor and Pi3-Kinase Inhibitor Bez235 and the Pi3-Kinase Inhibitor Bkm120 in Hepatocellular Carcinoma. Liver Int. 2013;33(5):780-93.

Dayoub R, Vogel A, Schuett J, Lupke M, Spieker SM, Kettern N, Hildt E, Melter M, Weiss TS. Nrf2 Activates Augmenter of Liver Regeneration (Alr) Via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration. Mol Med. 2013;19:237-44.

Buitrago-Molina LE, Marhenke S, Longerich T, Sharma AD, Boukouris AE, Geffers R, Guigas B, Manns MP, Vogel A. The Degree of Liver Injury Determines the Role of P21 in Liver Regeneration and Hepatocarcinogenesis in Mice. Hepatology. 2013;58(3):1143-52.

Breitbart A, Scharf GM, Duncker D, Widera C, Gottlieb J, Vogel A, Schmidt S, Brandes G, Heuft HG, Lichtinghagen R, Kempf T, Wollert KC, Bauersachs J, Heineke J. Highly Specific Detection of Myostatin Prodomain by an Immunoradiometric Sandwich Assay in Serum of Healthy Individuals and Patients. PLoS One. 2013;8(11):e80454.

2006 - 2012

2009

Schungel S, Buitrago-Molina LE, Nalapareddy P, Lebofsky M, Manns MP, Jaeschke H, Gross A, Vogel A. The Strength of the Fas Ligand Signal Determines Whether Hepatocytes Act as Type 1 or Type 2 Cells in Murine Livers. Hepatology. 2009;50(5):1558-66. Epub 2009/08/28.

Nalapareddy P, Schungel S, Hong JY, Manns MP, Jaeschke H, Vogel A. The Bh3-Only Protein Bid Does Not Mediate Death-Receptor-Induced Liver Injury in Obstructive Cholestasis. Am J Pathol. 2009;175(3):1077-85. Epub 2009/08/08.

Buitrago-Molina LE, Pothiraju D, Lamle J, Marhenke S, Kossatz U, Breuhahn K, Manns MP, Malek N, Vogel A. Rapamycin Delays Tumor Development in Murine Livers by Inhibiting Proliferation of Hepatocytes with DNA Damage. Hepatology. 2009;50(2):500-9.

2008

Willenbring H, Sharma AD, Vogel A, Lee AY, Rothfuss A, Wang Z, Finegold M, Grompe M. Loss of P21 Permits Carcinogenesis from Chronically Damaged Liver and Kidney Epithelial Cells Despite Unchecked Apoptosis. Cancer Cell. 2008;14(1):59-67. Epub 2008/07/05.

Sharma AD, Cantz T, Vogel A, Schambach A, Haridass D, Iken M, Bleidissel M, Manns MP, Scholer HR, Ott M. Murine Embryonic Stem Cell-Derived Hepatic Progenitor Cells Engraft in Recipient Livers with Limited Capacity of Liver Tissue Formation. Cell Transplant. 2008;17(3):313-23.

Marhenke S, Lamle J, Buitrago-Molina LE, Canon JM, Geffers R, Finegold M, Sporn M, Yamamoto M, Manns MP, Grompe M, Vogel A. Activation of Nuclear Factor E2-Related Factor 2 in Hereditary Tyrosinemia Type 1 and Its Role in Survival and Tumor Development. Hepatology. 2008;48(2):487-96. Epub 2008/07/31.

Lamle J, Marhenke S, Borlak J, von Wasielewski R, Eriksson CJ, Geffers R, Manns MP, Yamamoto M, Vogel A. Nuclear Factor-Eythroid 2-Related Factor 2 Prevents Alcohol-Induced Fulminant Liver Injury. Gastroenterology. 2008;134(4):1159-68.

2006

Vogel A, Aslan JE, Willenbring H, Klein C, Finegold M, Mount H, Thomas G, Grompe M. Sustained Phosphorylation of Bid Is a Marker for Resistance to Fas-Induced Apoptosis During Chronic Liver Diseases. Gastroenterology. 2006;130(1):104-19.

2004

Vogel A, van Den Berg IE, Al-Dhalimy M, Groopman J, Ou CN, Ryabinina O, Iordanov MS, Finegold M, Grompe M. Chronic Liver Disease in Murine Hereditary Tyrosinemia Type 1 Induces Resistance to Cell Death. Hepatology. 2004;39(2):433-43. Epub 2004/02/10.

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