Hepatic Cell Transplantation and Genetic Manipulation

Objectives

We aim to

  • Generate functional human hepatocytes by transcription factor (TF) based transprogramming for in vitro toxicology, transplantation and tissue engineering.
  • Establish novel transplantation methods for re-programmed and iPSC derived hepatocytes.
  • Develop in vivo CRISP/R-Cas9-AAV and lentivirus-based gene therapies for inherited metabolic liver diseases for clinical application.
  • RNA- based therapies for liver diseases

Research Focus

We have recently established a protocol for transcription factor (TF) programming of human fibroblasts into hepatocyte-like cells. Principal component analysis of the transcriptome shows a shift in global gene expression towards primary hepatocytes. The cells secrete albumin, express various Cytochrom P450 activities and express many liver specific metabolic enzymes. In our current program we aim to further refine the protocol by testing over-expression of other TF candidates and also miRNA´s and to demonstrate fully functional xenobiotic activity for in vitro testing of drugs and toxins. The program has also been extended to direct reprogramming of profibrogenic myofibroblasts into hepatocytes in vivo for therapeutic remodeling of chronic liver diseases.

Therapeutic transplantation of hepatocyte like cells derived from ES or iPS cells in to the liver remains difficult, since these cells engraft poorly in the target organ. We have developed novel transplantation techniques including targeted ablation of resident hepatocytes to induce expansion of gene corrected transplanted cells. Proof of principle has already been demonstrated with primary mouse hepatocytes. In our future work we will also examine, whether iPSC or ES derived hepatocytes can integrate into and repopulate Fah(-/-) mouse livers using the cell sheet technologies. We have recently generated AAV8 vectors for targeted CRISP/R-Cas9 mediated correction of the FAH gene in Fah(-/-) with high degrees of homology directed repair. Future studies will focus on increasing the efficacy of gene repair in the liver in vivo and on novel application technologies, which would be suitable for clinical application. We finally develop RNA based therapies for a variety of liver diseases based on RNA replicon technologies and non-viral delivery methods for RNA molecules.

Collaborations

Publications

2013 - ongoing

2018

Junge N, Yuan Q, Vu TH, Krooss S, Bednarski C, Balakrishnan A, Cathomen T, Manns MP, Baumann U, Sharma AD, Ott M. Homologous recombination mediates stable Fah gene integration and phenotypic correction in tyrosinaemia mouse-model. World Journal of Hepatology. 2018;10(2):277-86.

Lipps C, Klein F, Wahlicht T, Seiffert V, Butueva M, Zauers J, Truschel T, Luckner M, Köster M, MacLeod R, Pezoldt J, Hühn J, Yuan Q, Müller PP, Kempf H, Zweigerdt R, Dittrich-Breiholz O, Pufe T, Beckmann R, Drescher W, Riancho J, Sañudo C, Korff T, Opalka B, Rebmann V, Göthert JR, Alves PM, Ott M, Schucht R, Hauser H, Wirth D, May T. Expansion of functional personalized cells with specific transgene combinations. Nature Communications. 2018;9(1):994.

Xie Y, Zhang H, Guo X-J, Feng Y-C, He R-Z, Li X, Yu S, Zhao Y, Shen M, Zhu F, Wang X, Wang M, Balakrishnan A, Ott M, Peng F, Qin R-Y. Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites. Cell Death & Disease. 2018;9(2):249.

Ciccocioppo R, Dos Santos CC, Baumgart DC, Cangemi GC, Cardinale V, Ciacci C, De Coppi P, Haldar D, Klersy C, Nostro MC, Ott M, Piemonti L, Tomei AA, Uygun B, Vetrano S, Orlando G. Proceedings of the signature series event of the international society for cellular therapy: “Advancements in cellular therapies and regenerative medicine in digestive diseases,” London, United Kingdom, May 3, 2017. Cytotherapy. 2018;20(3):461-76.

Junge N, Sharma AD, Ott M. About cytokeratin 19 and the drivers of liver regeneration. Journal of Hepatology. 2018;68(1):5-7.

2017

Kirschning A, Liang Wang L, Seidel K, Ott M, Balakrishnan A, Komoll RM, Janko C, Alexiou C. Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo2017

2016

Wang LL, Balakrishnan A, Bigall NC, Candito D, Miethe Jan F, Seidel K, Xie Y, Ott M, Kirschning A. A Bio‐Chemosynthetic Approach to Superparamagnetic Iron Oxide–Ansamitocin Conjugates for Use in Magnetic Drug Targeting. Chemistry A European Journal. 2016;23(10):2265-70.

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.

Wang LL, Balakrishnan A, Bigall NC, Candito D, Miethe JF, Seidel K, Xie Y, Ott M, Kirschning A. A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide-Ansamitocin Conjugates for Use in Magnetic Drug Targeting. Chemistry. 2016.

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.

Hubner J, Hoseini SS, Suerth JD, Hoffmann D, Maluski M, Herbst J, Maul H, Ghosh A, Eiz-Vesper B, Yuan Q, Ott M, Heuser M, Schambach A, Sauer MG. Generation of Genetically Engineered Precursor T-Cells From Human Umbilical Cord Blood Using an Optimized Alpharetroviral Vector Platform. Molecular therapy : the journal of the American Society of Gene Therapy. 2016;24(7):1216-26.

2015

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.

Junge N, Mingozzi F, Ott M, Baumann U. Adeno-Associated Virus Vector-Based Gene Therapy for Monogenetic Metabolic Diseases of the Liver. J Pediatr Gastroenterol Nutr. 2015;60(4):433-40.

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

Ott M, Cantz T, Schneider A, Manns MP. [Diagnosis and Therapies for Acute Liver Failure: Scientific Developments]. Internist (Berl). 2014;55(11):1288-95. Diagnostik und Behandlung des akuten Leberversagens: Wissenschaftliche Entwicklungen.

Berneman-Zeitouni D, Molakandov K, Elgart M, Mor E, Fornoni A, Dominguez MR, Kerr-Conte J, Ott M, Meivar-Levy I, Ferber S. The Temporal and Hierarchical Control of Transcription Factors-Induced Liver to Pancreas Transdifferentiation. PLoS One. 2014;9(2):e87812.

Anggakusuma, Colpitts CC, Schang LM, Rachmawati H, Frentzen A, Pfaender S, Behrendt P, Brown RJ, Bankwitz D, Steinmann J, Ott M, Meuleman P, Rice CM, Ploss A, Pietschmann T, Steinmann E. Turmeric Curcumin Inhibits Entry of All Hepatitis C Virus Genotypes into Human Liver Cells. Gut. 2014;63(7):1137-49. Epub 2013/08/02.

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. Epub 2013/04/16.

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.

Rittelmeyer I, Rothe M, Brugman MH, Iken M, Schambach A, Manns MP, Baum C, Modlich U, Ott M. Hepatic Lentiviral Gene Transfer Is Associated with Clonal Selection, but Not with Tumor Formation in Serially Transplanted Rodents. Hepatology. 2013;58(1):397-408.

Norenberg A, Heinz S, Scheller K, Hewitt NJ, Braspenning J, Ott M. Optimization of Upcyte(R) Human Hepatocytes for the in Vitro Micronucleus Assay. Mutat Res. 2013;758(1-2):69-79.

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. Epub 2013/08/09.

Abel T, El Filali E, Waern J, Schneider IC, Yuan Q, Munch RC, Hick M, Warnecke G, Madrahimov N, Kontermann RE, Schuttrumpf J, Muller UC, Seppen J, Ott M, Buchholz CJ. Specific Gene Delivery to Liver Sinusoidal and Artery Endothelial Cells. Blood. 2013;122(12):2030-8.

2006 - 2012

2012

Waern JM, Yuan Q, Rudrich U, Becker PD, Schulze K, Strick-Marchand H, Huntington ND, Zacher BJ, Wursthorn K, DiSanto JP, Guzman CA, Manns MP, Ott M, Bock M. Ectopic Expression of Murine Cd47 Minimizes Macrophage Rejection of Human Hepatocyte Xenografts in Immunodeficient Mice. Hepatology. 2012;56(4):1479-88.

Rothe M, Rittelmeyer I, Iken M, Rudrich U, Schambach A, Glage S, Manns MP, Baum C, Bock M, Ott M, Modlich U. Epidermal Growth Factor Improves Lentivirus Vector Gene Transfer into Primary Mouse Hepatocytes. Gene Ther. 2012;19(4):425-34. Epub 2011/08/19.

Kafert-Kasting S, Schneider A, Attaran M, Priesner C, Barthold M, Perrier AL, Kriegbaum H, Ott M, Meyburg J. Safety Assessment of Intraportal Liver Cell Application in New Zealand White Rabbits under Glp Conditions. Arch Toxicol. 2012;86(9):1413-22.

Bieback K, Wuchter P, Besser D, Franke W, Becker M, Ott M, Pacher M, Ma N, Stamm C, Kluter H, Muller A, Ho AD, consortium S-M. Mesenchymal Stromal Cells (Mscs): Science and F(R)Iction. J Mol Med (Berl). 2012;90(7):773-82.

2011

Straub BK, Rickelt S, Zimbelmann R, Grund C, Kuhn C, Iken M, Ott M, Schirmacher P, Franke WW. E-N-Cadherin Heterodimers Define Novel Adherens Junctions Connecting Endoderm-Derived Cells. J Cell Biol. 2011;195(5):873-87. Epub 2011/11/23.

Sharma AD, Narain N, Handel EM, Iken M, Singhal N, Cathomen T, Manns MP, Scholer HR, Ott M, Cantz T. Microrna-221 Regulates Fas-Induced Fulminant Liver Failure. Hepatology. 2011;53(5):1651-61.

Sancho-Bru P, Roelandt P, Narain N, Pauwelyn K, Notelaers T, Shimizu T, Ott M, Verfaillie C. Directed Differentiation of Murine-Induced Pluripotent Stem Cells to Functional Hepatocyte-Like Cells. J Hepatol. 2011;54(1):98-107.

Koenig S, Yuan Q, Krause P, Christiansen H, Rave-Fraenk M, Kafert-Kasting S, Kriegbaum H, Schneider A, Ott M, Meyburg J. Regional Transient Portal Ischemia and Irradiation as Preparative Regimen for Hepatocyte Transplantation. Cell Transplant. 2011;20(2):303-11. Epub 2010/08/20.

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. Epub 2011/11/15.

Iacob R, Rudrich U, Rothe M, Kirsch S, Maasoumy B, Narain N, Verfaillie CM, Sancho-Bru P, Iken M, Popescu I, Schambach A, Manns MP, Bock M. Induction of a Mature Hepatocyte Phenotype in Adult Liver Derived Progenitor Cells by Ectopic Expression of Transcription Factors. Stem Cell Res. 2011;6(3):251-61.

Ciesek S, von Hahn T, Colpitts CC, Schang LM, Friesland M, Steinmann J, Manns MP, Ott M, Wedemeyer H, Meuleman P, Pietschmann T, Steinmann E. The Green Tea Polyphenol, Epigallocatechin-3-Gallate, Inhibits Hepatitis C Virus Entry. Hepatology. 2011;54(6):1947-55.

Wu G, Liu N, Rittelmeyer I, Sharma AD, Sgodda M, Zaehres H, Bleidissel M, Greber B, Gentile L, Han DW, Rudolph C, Steinemann D, Schambach A, Ott M, Scholer HR, Cantz T. Generation of Healthy Mice from Gene-Corrected Disease-Specific Induced Pluripotent Stem Cells. PLoS Biol. 2011;9(7):e1001099.

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