Hepatic Cell Therapy: Patient Liver Stem Cells

Objectives

The ultimate aim of the RG is to treat patients with liver diseases by the means of hepatic cell therapy as a substitute for whole organ transplantation whenever suitable. Ideally, those cells would be from the patient himself - either hepatocytes propagated and gene therapeutically manipulated ex vivo, or other cell types from biopsies differentiated towards hepatocytes. A second goal is the development of a tissue culture system for primary human hepatocytes for in vitro (high throughput) drug and drug toxicity testings.

Research Focus

Based on our advances in improving tissue culture conditions we are working on the in vitro propagation of primary hepatocytes. Starting from small, patient specific samples from biopsies we aim to have high numbers of hepatocytes available for in vitro (gene therapeutic) manipulation, subsequent cell therapeutic transplantation and also for in vitro maturation for drug testing. In cases of severe liver damage there will not be sufficient numbers of hepatocytes available from liver biopsies for in vitro popagation and cell repair. Thus we set out to develop ways to transdifferentiate Mesenchymal Stromal Cells - a easily accessible cell source from adipose tissue or bone marrow of the patient - towards hepatocytes. With respect to the transplantation aspect of cell therapy we work on the establishment/improvement of mouse model systems with human-mouse chimeric livers. These model systems can be used to strengthen the competitive capabilities of the transplanted cells against the recipients resident liver cells and their maturation/functionality in the target organ. Furthermore, gene therapeutic approaches - introducing repair functions into hepatocytes prior to transplantation via lentiviral gene transfer - are investigated.

Collaborations

  • Dr. Laszlo Sajti, RG Nanomaterials, LZH: Nanoparticles specific for hepatocyte subpopulations
  • Dr. Florian Vondran, ReMediES, MHH: Primary Hepatocytes
  • PD Dr. Arndt Vogel, Dept. of Gastroenterology, MHH: Transplantation of adult hepatocyte progenitors
  • Dr. Dr. Axel Schambach, REBIRTH JRG Hematopoietic Cell Therapy: Lentiviral gene transfer
  • Prof. Lars Zender, REBIRTH RG Liver Regeneration: Proliferation/Maturation inducing genes
  • Dr. Tobias Cantz, REBIRTH JRG Stem Cell Biology: Hepatocyte differentiation from stem cell sources
  • Prof. Carlos Guzman, Department of Vaccinology and Applied Microbiology, HZI, Braunschweig: Mouse models with human-mouse chimeric livers
  • Prof. Thomas Pietschmann, Division of Experimental Virology, Twincore, Hannover: Hepatocytes and HCV replication

Further Research Projects

  • SFB 738 ‘Lentiviral- induced Insertional Mutagenesis in the Gene Therapy of Liver Diseases’
  • German Federal Ministry of Education and Research (BMBF) project ‘Start-MSC 2’
  • BMBF project ‘Novel Mouse Model System for Testing HIV and HCV Vaccines’

Publications

2013 - ongoing

2017

Junge N, Sharma AD, Ott M. About cytokeratin 19 and the drivers of liver regeneration. J Hepatol. 2017. Epub 2017/10/17.

Sgodda M, Dai Z, Zweigerdt R, Sharma AD, Ott M, Cantz T. A Scalable Approach for the Generation of Human Pluripotent Stem Cell-Derived Hepatic Organoids with Sensitive Hepatotoxicity Features. Stem Cells Dev. 2017/07/13 ed2017. p. 1490-504.

Seidel K, Balakrishnan A, Alexiou C, Janko C, Komoll RM, Wang LL, Kirschning A, Ott M. Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo. Chemistry. 2017/06/07 ed2017. p. 12326-37.

2016

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. 2016/12/10 ed2017. p. 2265-70.

2015

Goldhafer F, Bock M, Falk CS, Vondran FWR. Immunological Aspects of Liver Cell Transplantation. World Journal of Transplantation. 2015.

Colleypriest BJ, Burke ZD, Leonard P, Griffiths LP, Chen Y, Yu W-Y, Jover R, Bock M, Biddlestone L, Quinlan JM, Ward SG, Farrant JM, Slack JMW, Tosh D. Hnf4α is a master gene that can generate columnar metaplasia in oesophageal epithelium. 2015.

2014

Taranta A, Rogalska-Taranta M, Gutierrez R, Manns MP, Bock M, Wursthorn K. Rapid Hepatitis B and Hepatitis Delta Virus Rna Quantification from Small-Sized Liver Tissue Samples. J Clin Virol. 2014;61(2):286-8.

Riedel G, Rudrich U, Fekete-Drimusz N, Manns MP, Vondran FW, Bock M. An Extended Deltact-Method Facilitating Normalisation with Multiple Reference Genes Suited for Quantitative Rt-Pcr Analyses of Human Hepatocyte-Like Cells. PLoS One. 2014;9(3):e93031.

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.

2011

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.

2009

Sancho-Bru P, Najimi M, Caruso M, Pauwelyn K, Cantz T, Forbes S, Roskams T, Ott M, Gehling U, Sokal E, Verfaillie CM, Muraca M. Stem and Progenitor Cells for Liver Repopulation: Can We Standardise the Process from Bench to Bedside? Gut. 2009;58(4):594-603. Epub 2008/12/19.

Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, Schmidt J, Ott M, Pettenazzo A, Luecke T, Bertram H, Hoffmann GF, Burlina A. One Liver for Four Children: First Clinical Series of Liver Cell Transplantation for Severe Neonatal Urea Cycle Defects. Transplantation. 2009;87(5):636-41.

Haridass D, Yuan Q, Becker PD, Cantz T, Iken M, Rothe M, Narain N, Bock M, Norder M, Legrand N, Wedemeyer H, Weijer K, Spits H, Manns MP, Cai J, Deng H, Di Santo JP, Guzman CA, Ott M. Repopulation Efficiencies of Adult Hepatocytes, Fetal Liver Progenitor Cells, and Embryonic Stem Cell-Derived Hepatic Cells in Albumin-Promoter-Enhancer Urokinase-Type Plasminogen Activator Mice. Am J Pathol. 2009;175(4):1483-92.

2008

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.

2006

Jochheim-Richter A, Rudrich U, Koczan D, Hillemann T, Tewes S, Petry M, Kispert A, Sharma AD, Attaran F, Manns MP, Ott M. Gene Expression Analysis Identifies Novel Genes Participating in Early Murine Liver Development and Adult Liver Regeneration. Differentiation. 2006;74(4):167-73.

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