miRNA in Liver Regeneration

Objectives

Our scientific vision is to achieve treatment of end-stage liver diseases, through interdisciplinary collaborations among REBIRTH research groups. The identification of novel cues that enable generation, expansion and proliferation of hepatocytes hold immense potential for the treatment of end stage liver diseases. Specifically, we are investigating novel regulatory molecules such as microRNAs (miRNAs) and transcription factors in liver regeneration and hepatocyte differentiation using novel cell and molecular biology techniques.

Research Focus

Compelling evidence from mouse liver regeneration and serial transplantation studies strongly indicates that adult hepatocytes retain their ability to proliferate in vivo. We seek to understand hepatocyte proliferation at the molecular level with a specific focus on miRNAs. We aim to harness the potential of miRNAs for improving hepatocyte proliferation in vitro and in vivo. Another focus of our research group is to improve hepatocyte differentiation from stem cells sources using miRNAs and transcription factors as modulators of hepatocyte differentiation.

Our interdisciplinary collaborations with other REBIRTH research groups, provides us with valuable tools and resources to achieve our objectives and expand our research focus.

Collaborations

Awards

  • A. Sharma, German association of study of liver diseases “(GASL)-Prize of YAEL Foundation” 2017.
  • A. Sharma, “Publication of the year award” by German Stem Cell Network 2016 (Publication: Direct reprogramming of hepatic myofibroblasts into heptocytes in vivo attenuates liver fibrosis. Cell Stem Cell, 2016).
  • D. Yang, HBRS Best PhD Prize, 2016.
  • A. Sharma, travel grant at the FASEB liver conference, Florida, USA 2016.
  • G. Song, travel grant at the FALK symposium, Düsseldorf, 2016.
  • J. Tsay, travel grant at the EASL, Spain, 2016.
  • M. Farid, travel grant at the EASL, Spain, 2016.
  • A. Sharma, award from “Gilead Sciences International Research Scholars Program in liver diseases” 2013.
  • S. Möbus, poster award at the “MicroRNAs Europe & Single Molecule Biology Europe-Meeting” 2012.
  • A. Sharma, poster award at the “17th HILF symposium MHH” 2011.

Teaching

  • Lecturer in the Regenerative Medicine PhD program.

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.

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.

Lim KT, Lee SC, Gao Y, Kim KP, Song G, An SY, Adachi K, Jang YJ, Kim J, Oh KJ, Kwak TH, Hwang SI, You JS, Ko K, Koo SH, Sharma AD, Kim JH, Hui L, Cantz T, Scholer HR, Han DW. Small Molecules Facilitate Single Factor-Mediated Hepatic Reprogramming. Cell reports. 2016.

2015

Mattis AN, Song G, Hitchner K, Kim RY, Lee AY, Sharma AD, Malato Y, McManus MT, Esau CC, Koller E, Koliwad S, Lim LP, Maher JJ, Raffai RL, Willenbring H. A Screen in Mice Uncovers Repression of Lipoprotein Lipase by Microrna-29a as a Mechanism for Lipid Distribution Away from the Liver. Hepatology. 2015;61(1):141-52. Epub 2014/08/19.

2014

Möbus 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. Epub 2014/08/20.

Cantz T, Sharma AD, Ott M. Concise Review: Cell Therapies for Hereditary Metabolic Liver Diseases - Concepts, Clinical Results and Future Developments. Stem Cells. 2014. Epub 2014/12/20.

2013

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. Epub 2013/03/26.

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.

Sgodda M, Möbus 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. Epub 2013/05/07.

Yuan Q, Loya K, Rani B, Möbus 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. Epub 2012/07/24.

2006 - 2012

2011

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. Epub 2011/03/15.

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. Epub 2011/07/19.

Saunders LR, Sharma AD, Tawney J, Nakagawa M, Okita K, Yamanaka S, Willenbring H, Verdin E. miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues. Aging (Albany NY). 2010;2(7):415-31. Epub 2010/07/17.

Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH, Frandsen NM, Willenbring H. MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology. 2010;51(5):1735-43. Epub 2010/05/01.

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.

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.

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. Epub 2006/05/11.

Sharma AD, Cantz T, Manns MP, Ott M. The role of stem cells in physiology, pathophysiology, and therapy of the liver. Stem Cell Rev. 2006;2(1):51-8. Epub 2006/12/05.

Sharma AD, Cantz T, Richter R, Eckert K, Henschler R, Wilkens L, Jochheim-Richter A, Arseniev L, Ott M. Human cord blood stem cells generate human cytokeratin 18-negative hepatocyte-like cells in injured mouse liver. Am J Pathol. 2005;167(2):555-64. Epub 2005/07/29.

Cantz T, Sharma AD, Jochheim-Richter A, Arseniev L, Klein C, Manns MP, Ott M. Reevaluation of bone marrow-derived cells as a source for hepatocyte regeneration. Cell Transplantation. 2004;13(6):659-66. Epub 2005/01/15.

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