Hepatobiliary Regeneration

Objectives

Figure 1 (left) & Figure 2 (right)

Molecular and Cellular Mechanism of Biliary Regeneration and Differentiation

Biliary Regeneration is an underinvestigated issue in liver regeneration upon acute and chronic liver damage. Noteworthy, misregulation of bile duct homeostasis is one of the major causes of chronic liver graft failure, known as ischemic-type biliary lesions (ITBL), after liver transplantation. Multiple other critical conditions can lead to secondary sclerosing cholangitis (SSC) exhibiting severe bile duct destruction (Fig. 1).

In our collaborative project we will elucidate the endogenous regeneration of bile duct cells form common hepatic progenitor cells, i.e. the differentiation of stem cells into functional bile duct cells in vitro and in vivo. Furthermore, we will analyze the molecular regulation of bile duct regeneration after liver damage (metabolic liver damage, partial hepatectomy, toxic injury) in our experimental models and in clinical specimens. Both approaches aim for novel therapeutic approaches for the prevention and treatment of bile duct-associated pathologies (Fig. 2).

Research Focus

Corner Stones of Hepatobiliary Regeneration

Within the REBIRTH cluster our three groups (Units 1.1, 3.1 and 3.3) actively collaborate in various projects with a strong focus on hepatic stem cell biology, hepatic cell transplantation, and liver regeneration. In particular, we have comprehensive expertise in endoderm differentiation of pluripotent stem cells, in molecular characterization of liver regeneration and in manipulating hepatic regeneration by means of microRNAs and shRNAs transfection in vivo and in vitro.

Biliary Differentiation from Hepatic Precursor Cells

With respect to biliary differentiation we will establish protocols to isolate und propagate biliary cells from murine livers and evaluate protocols for the differentiation of stem cell-derived bipotent hepatic progenitor cells into biliary cells. Furthermore, we will analyse microRNA profiles of stem cell-derived biliary cells in comparison to undifferentiated pluripotent stem cells, fetal progenitor cells and mature bile duct cells to identify microRNAs that promote and maintain biliary differentiation capabilities.

Molecular Characterization of Biliary Regeneration

In our established experimental models of biliary disorders (Mdr2-/--mice, toxic injury: DDC/CDE diet) gene expression profile will be performed to identify relevant biliary genes and microRNAs during hepatobiliary regeneration. This data will be correlated to data from clinical specimens, obtain from patients suffering from secondary sclerosing cholangitis (SSC), ischemia-type biliary lesions (ITBL) and other biliary disorders.

Tissue-specific expression of transgenes and small RNAs in Bile Duct Cells

In previous experiments a transductions systems for bile duct cells was established, which takes advantage of a biliary promoter driving the transgene expression. This construct can be applied in vitro and in vivo using an Adeno- Associated Virus 8 (AAV8) vector system.

Collaborations

Publications

2013 - ongoing

2017

Hoepfner J, Kleinsorge M, Papp O, Alfken S, Heiringhoff R, Pich A, Sauer V, Zibert A, Gohring G, Schmidt H, Sgodda M, Cantz T. In vitro modelling of familial amyloidotic polyneuropathy allows quantitative detection of transthyretin amyloid fibril-like structures in hepatic derivatives of patient-specific induced pluripotent stem cells. Biol Chem. 2017.

2016

Yang D, Yuan Q, Balakrishnan A, Bantel H, Klusmann JH, Manns MP, Ott M, Cantz T, Sharma AD. MicroRNA-125b-5p mimic inhibits acute liver failure. Nature communications. 2016;7:11916.

Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, Reetz J, Brandes S, Dai Z, Putzer BM, Arauzo-Bravo MJ, Steinemann D, Luedde T, Schwabe RF, Manns MP, Scholer HR, Schambach A, Cantz T, Ott M, Sharma AD. Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis. Cell stem cell. 2016;18(6):797-808.

Hoepfner J, Kleinsorge M, Papp O, Ackermann M, Alfken S, Rinas U, Solodenko W, Kirschning A, Sgodda M, Cantz T. Biphasic modulation of Wnt signaling supports efficient foregut endoderm formation from human pluripotent stem cells. Cell Biol Int. 2016;40(5):534-48.

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.

Eggenschwiler R, Moslem M, Fraguas MS, Galla M, Papp O, Naujock M, Fonfara I, Gensch I, Wahner A, Beh-Pajooh A, Mussolino C, Tauscher M, Steinemann D, Wegner F, Petri S, Schambach A, Charpentier E, Cathomen T, Cantz T. Improved bi-allelic modification of a transcriptionally silent locus in patient-derived iPSC by Cas9 nickase. Scientific reports. 2016;6:38198.

2015

Cantz T. Die Erzeugung von Gameten aus pluripotenten Stammzellen. In: Heinemann T, Dederer H-G, Cantz T, editors. Entwicklungsbiologische Totipotenz in Ethik und Recht. Göttingen: V&R unipress; 2014. p. 57-65.

Advena-Regnery B, Böhm K, Jung B, Rottländer K, Sgodda S (2015). Sind Parthenoten Embryonen? Zur biologischen und normativen Einordnung von menschlichen Parthenoten. Zeitschrift für medizinische Ethik. 61:63-79.

Rahman SH, Kuehle J, Reimann C, Mlambo T, Alzubi J, Maeder ML, Riedel H, Fisch P, Cantz T, Rudolph C, Mussolino C, Joung JK, Schambach A, Cathomen T. Rescue of DNA-Pk Signaling and T-Cell Differentiation by Targeted Genome Editing in a Prkdc Deficient Ipsc Disease Model. PLoS Genet. 2015;11(5):e1005239.

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.

Moslem M, Eberle I, Weber I, Henschler R, Cantz T. Mesenchymal Stem/Stromal Cells Derived from Induced Pluripotent Stem Cells Support Cd34(Pos) Hematopoietic Stem Cell Propagation and Suppress Inflammatory Reaction. Stem Cells Int. 2015;2015:843058. Epub 2015/07/18.

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.

Kim J, Kim KP, Lim KT, Lee SC, Yoon J, Song G, Hwang SI, Scholer HR, Cantz T, Han DW. Generation of Integration-Free Induced Hepatocyte-Like Cells from Mouse Fibroblasts. Sci Rep. 2015;5:15706.

Katsirntaki K, Mauritz C, Olmer R, Schmeckebier S, Sgodda M, Puppe V, Eggenschwiler R, Duerr J, Schubert SC, Schmiedl A, Ochs M, Cantz T, Salwig I, Szibor M, Braun T, Rathert C, Martens A, Mall MA, Martin U. Bronchoalveolar Sublineage Specification of Pluripotent Stem Cells: Effect of Dexamethasone Plus Camp-Elevating Agents and Keratinocyte Growth Factor. Tissue Eng Part A. 2015;21(3-4):669-82.

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.

Cantz T, Sharma AD, Ott M. Concise Review: Cell Therapies for Hereditary Metabolic Liver Diseases-Concepts, Clinical Results, and Future Developments. Stem Cells. 2015;33(4):1055-62.

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.

Lachmann N, Happle C, Ackermann M, Luttge D, Wetzke M, Merkert S, Hetzel M, Kensah G, Jara-Avaca M, Mucci A, Skuljec J, Dittrich AM, Pfaff N, Brennig S, Schambach A, Steinemann D, Gohring G, Cantz T, Martin U, Schwerk N, Hansen G, Moritz T. Gene Correction of Human Induced Pluripotent Stem Cells Repairs the Cellular Phenotype in Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2014;189(2):167-82.

Ackermann M, Lachmann N, Hartung S, Eggenschwiler R, Pfaff N, Happle C, Mucci A, Gohring G, Niemann H, Hansen G, Schambach A, Cantz T, Zweigerdt R, Moritz T. Promoter and Lineage Independent Anti-Silencing Activity of the A2 Ubiquitous Chromatin Opening Element for Optimized Human Pluripotent Stem Cell-Based Gene Therapy. Biomaterials. 2014;35(5):1531-42.

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.

Sgodda M, Mobus S, Hoepfner J, Sharma AD, Schambach A, Greber B, Ott M, Cantz T. Improved Hepatic Differentiation Strategies for Human Induced Pluripotent Stem Cells. Curr Mol Med. 2013;13(5):842-55.

Sgodda M, Cantz T. Small but Significant: Inter- and Intrapatient Variations in Ips Cell-Based Disease Modeling. Mol Ther. 2013;21(1):5-7. Epub 2013/01/03.

Schmeckebier S, Mauritz C, Katsirntaki K, Sgodda M, Puppe V, Duerr J, Schubert SC, Schmiedl A, Lin Q, Palecek J, Draeger G, Ochs M, Zenke M, Cantz T, Mall MA, Martin U. Keratinocyte Growth Factor and Dexamethasone Plus Elevated Camp Levels Synergistically Support Pluripotent Stem Cell Differentiation into Alveolar Epithelial Type Ii Cells. Tissue Engineering Part A. 2013;19(7-8):938-51.

Pfaff N, Lachmann N, Ackermann M, Kohlscheen S, Brendel C, Maetzig T, Niemann H, Antoniou MN, Grez M, Schambach A, Cantz T, Moritz T. A Ubiquitous Chromatin Opening Element Prevents Transgene Silencing in Pluripotent Stem Cells and Their Differentiated Progeny. Stem Cells. 2013;31(3):488-99.

Pfaff N, Cantz T. From Skin to Blood: A New Member Joins the Iclub. Cell Stem Cell. 2013;13(2):131-3.

Gross B, Sgodda M, Rasche M, Schambach A, Gohring G, Schlegelberger B, Greber B, Linden T, Reinhardt D, Cantz T, Klusmann JH. Improved Generation of Patient-Specific Induced Pluripotent Stem Cells Using a Chemically-Defined and Matrigel-Based Approach. Curr Mol Med. 2013;13(5):765-76.

Eggenschwiler R, Loya K, Wu G, Sharma AD, Sgodda M, Zychlinski D, Herr C, Steinemann D, Teckman J, Bals R, Ott M, Schambach A, Scholer HR, Cantz T. Sustained Knockdown of a Disease-Causing Gene in Patient-Specific Induced Pluripotent Stem Cells Using Lentiviral Vector-Based Gene Therapy. Stem Cells Transl Med. 2013;2(9):641-54.

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.

2006 - 2012

2012

Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL. A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage. Cell. 2012;148(5):1001-14.

Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L, Kress TR, Muthalagu N, Rycak L, Rudalska R, Moll R, Kempa S, Zender L, Eilers M, Murphy DJ. Deregulated Myc Expression Induces Dependence Upon Ampk-Related Kinase 5. Nature. 2012;483(7391):608-12.

2011

Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L. Senescence Surveillance of Pre-Malignant Hepatocytes Limits Liver Cancer Development. Nature. 2011;479(7374):547-51.

2010

Zender L, Villanueva A, Tovar V, Sia D, Chiang DY, Llovet JM. Cancer Gene Discovery in Hepatocellular Carcinoma. J Hepatol. 2010;52(6):921-9.

Wuestefeld T, Zender L. Dlc1 and Liver Cancer: The Akt Connection. Gastroenterology. 2010;139(4):1093-6.

Kühnel F, Gürlevik E, Wirth TC, Strüver N, Malek NP, Müller-Schilling M, Manns MP, Carnero A, Zender L, Kubicka S. Targeting of P53-Transcriptional Dysfunction by Conditionally Replicating Adenovirus Is Not Limited by P53-Homologues. Molecular Therapy. 2010;18(5):936-46.

Gurlevik E, Woller N, Struver N, Schache P, Kloos A, Manns MP, Zender L, Kuhnel F, Kubicka S. Selectivity of Oncolytic Viral Replication Prevents Antiviral Immune Response and Toxicity, but Does Not Improve Antitumoral Immunity. Mol Ther. 2010;18(11):1972-82.

2009

Zender L, Rudolph KL. Keeping Your Senescent Cells under Control. Aging (Albany NY). 2009;1(5):438-41.

Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM. Yes-Associated Protein Is an Independent Prognostic Marker in Hepatocellular Carcinoma. Cancer. 2009;115(19):4576-85. Epub 2009/06/25.

Schache P, Gurlevik E, Struver N, Woller N, Malek N, Zender L, Manns M, Wirth T, Kuhnel F, Kubicka S. Vsv Virotherapy Improves Chemotherapy by Triggering Apoptosis Due to Proteasomal Degradation of Mcl-1. Gene Ther. 2009;16(7):849-61. Epub 2009/04/17.

Ma O, Cai WW, Zender L, Dayaram T, Shen J, Herron AJ, Lowe SW, Man TK, Lau CC, Donehower LA. Mmp13, Birc2 (Ciap1), and Birc3 (Ciap2), Amplified on Chromosome 9, Collaborate with P53 Deficiency in Mouse Osteosarcoma Progression. Cancer Res. 2009;69(6):2559-67.

Liu LX, Lee NP, Chan VW, Xue W, Zender L, Zhang C, Mao M, Dai H, Wang XL, Xu MZ, Lee TK, Ng IO, Chen Y, Kung HF, Lowe SW, Poon RT, Wang JH, Luk JM. Targeting Cadherin-17 Inactivates Wnt Signaling and Inhibits Tumor Growth in Liver Carcinoma. Hepatology. 2009;50(5):1453-63.

Laska MJ, Lowe SW, Zender L, Hearn S, Vogel U, Jensen UB, Bric A, Nexo BA. Enforced Expression of Ppp1r13l Increases Tumorigenesis and Invasion through P53-Dependent and P53-Independent Mechanisms. Mol Carcinog. 2009;48(9):832-42. Epub 2009/03/06.

Gurlevik E, Woller N, Schache P, Malek NP, Wirth TC, Zender L, Manns MP, Kubicka S, Kuhnel F. P53-Dependent Antiviral Rna-Interference Facilitates Tumor-Selective Viral Replication. Nucleic Acids Res. 2009;37(12):e84.

Bric A, Miething C, Bialucha CU, Scuoppo C, Zender L, Krasnitz A, Xuan Z, Zuber J, Wigler M, Hicks J, McCombie RW, Hemann MT, Hannon GJ, Powers S, Lowe SW. Functional Identification of Tumor-Suppressor Genes through an in Vivo Rna Interference Screen in a Mouse Lymphoma Model. Cancer Cell. 2009;16(4):324-35. Epub 2009/10/06.

2008

Zender L, Xue W, Zuber J, Semighini CP, Krasnitz A, Ma B, Zender P, Kubicka S, Luk JM, Schirmacher P, McCombie WR, Wigler M, Hicks J, Hannon GJ, Powers S, Lowe SW. An Oncogenomics-Based in Vivo Rnai Screen Identifies Tumor Suppressors in Liver Cancer. Cell. 2008;135(5):852-64.

Xue W, Krasnitz A, Lucito R, Sordella R, Vanaelst L, Cordon-Cardo C, Singer S, Kuehnel F, Wigler M, Powers S, Zender L, Lowe SW. Dlc1 Is a Chromosome 8p Tumor Suppressor Whose Loss Promotes Hepatocellular Carcinoma. Genes Dev. 2008;22(11):1439-44. Epub 2008/06/04.

Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW. Senescence of Activated Stellate Cells Limits Liver Fibrosis. Cell. 2008;134(4):657-67.

2007

Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL. Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice. Cell. 2007;130(5):863-77.

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