Erdal Lab. on Stem Cell and Organoid Technologies

OVERVIEW

Liver stem cells (LSCs) are precursors of hepatoblasts, which are presumed to be the transit-amplifying cells that first give rise to committed progenitors, and then to hepatocytes and cholangiocytes. Liver stem/progenitor cells appear and undergo a massive expansion in chronic liver damage and become cancer stem cells (CSC) to further initiate tumor formation. These cells are also known to be responsible for tumor relapse, metastasis, and chemoresistance in liver cancer. Therefore, understanding how they form, how they are sustained and how to defeat them is among the most intensive areas of cancer research today. Additionally, liver stem/ progenitor cells are candidates for ex-vivo liver cell replacement as an alternative method to orthologous liver transplantation in the treatment of end-stage liver pathologies. Recent advances allow us to obtain patient’s hepatocytes derived from inducible pluripotent stem cells (iPSCs) reprogrammed from his own fibroblast and use them for tissue replacement and gene therapy. The first step of hepatic development from iPSCs is the induction of definitive endoderm containing liver stem/progenitor cells by using chemicals. Further treatment with some growth factors can then direct cells towards the hepatic lineage. Even if the limitations of technology still remain (i.e., the potential for teratoma formation and low efficiency), iPS-derived hepatocytes are a very promising population for cell therapies in hepatology.

RESEARCH INTERESTS

Our research concentrates on two main themes: 1.Understanding which and how molecular signaling events regulate the expansion and activation of EpCAM+/ CD133+ subset of liver stem/progenitor cells in the development of Hepatocellular Carcinoma (HCC), 2. Developing a method to produce highly pure, functional and fully-differentiated hepatocytes from non-transgenic iPSCs to be potentially used for cell-based therapies.

1. Hepatic Stem Cells in HCC: Here, we have two main lines of research First; we investigate the importance of pluripotency genes on the stem cell phenotype in HCC. The tumoral stem cell reprogramming hypothesis, i.e., the ability of stemness factors to redirect normal and differentiated tumor cells toward a less-differentiated and stem-like state, adds new layers of complexity to cancer biology; because the effects of such reprogramming may remain dormant until engaged later in response to (epi) genetic and/or (micro) environmental events. To test this hypothesis, we utilized an in vitro model of Oct4, Sox-2, KLF4 and c-myc (OSKM) overexpressing cancer stem cell (CSC)-like cellular state in HuH7 cell line. After overexpressing OSKM genes in non-hepatic stem cell population (EpCAM-/CD133- cells) we analyze cell behaviors such as proliferation, migration, EMT and in vivo tumor formation.

Secondly, we aim to understand the role of Polycomb repressive complex 2 (PRC2) on the expansion and activation of the EpCAM+/CD133+ subset of liver stem/progenitor cells in HCC.PRC2 has a crucial role in epigenetic gene silencing and regulation of developmental pathways. EZH2 encodes histone methyltransferase enzyme as the catalytic component of PRC2, creating H2K27Me3 histone mark which results in transcriptional silencing. EZH2 is overexpressed in HCC and mostly associated with the progression and aggressiveness of HCC. Our goal is to identify transcriptomal changes regulating H3K27Me3 mark on the liver cancer stem cells.

2. Stem Cell Based Therapies for Liver Diseases: Differentiated hepatocytes produced from a patient’s inducible pluripotent stem cells (iPSCs) have many potential therapeutic applications, including their use in tissue replacement and gene therapy as well as disease modeling. In our lab, disease-specific iPSC colonies have been reprogrammed chemically from skin fibroblasts isolated from urea cycle disease (Citrullinemia) patients, then produce iPSC-derived hepatocytes by optimized differentiation protocols. Further, a functional copy of the mutant gene will be transferred into such hepatocytes demonstrating proof of principle of an ex vivo gene therapy approach. Lastly, the corrected hepatocytes will be functionally validated in an in-vivo cell transplantation model.

Group Members

Erdal Lab. on Stem Cell and Organoid Technologies

Group Leader

Esra ERDAL
esra.erdal@ibg.edu.tr
+90 232 299 41 00 (5031)
+9 02322994153

Bilge KARAÇİÇEK Researcher  bilge.karacicek@ibg.edu.tr


Alper BAĞRIYANIK Research Group Member  alper.bagriyanik@ibg.edu.tr


Nur ARSLAN Research Group Member  nur.arslan@ibg.edu.tr


Soheil AKBARİ Post-doc Researcher  soheil.akbari@ibg.edu.tr


Nervin ERSOY Visiting Researcher  nevin.ersoy@msfr.ibg.edu.tr


Canan ÇELİKER MSc Student  canan.celiker@msfr.ibg.edu.tr


Kübra KAPLAN Graduate Student 


Emine Berna BIÇAK MSc Student  berna.bicak@msfr.ibg.edu.tr


Melis KANIK MSc Student  melis.kanik@msfr.ibg.edu.tr


Mustafa KARABİÇİCİ Ph.D. Student  mustafa.karabicici@msfr.ibg.edu.tr


Sadık BALKOZAK Undergraduate Student  sadik.balkozak@msfr.ibg.edu.tr


Selected Publications

Soheil Akbari, Gulben Gurhan Sevinc, Nevin Ersoy, Onur Başak, Kübra Kaplan, Kenan Sevinç, Erkin Özel, Berke Sengun, Eray Enustun, Burcu Özçimen, Alper Bağrıyanık, Nur Arslan, Tamer Onder, Esra Erdal. Robust, long-term culture of endoderm derived hepatic organoids (eHEPOs) for disease modeling. Stem Cell Reports. 2019 September. doi:10.1016/j.stemcr.2019.08.007.

Delman M, Avcı ST, Akçok İ, Kanbur T, Erdal E, Çağır A. Antiproliferative activity of (R)-4'-methylklavuzon on hepatocellular carcinoma cells and EpCAM+/CD133+ cancer stem cells via SIRT1 and Exportin-1 (CRM1) inhibition. European Journal of Medicinal Chemistry. 2019 October; 180: 224-237. doi:10.1016/j.ejmech.2019.07.024.

Yavuz Tokgöz, Cahit Barış Erdur, Soheil Akbari, Tuncay Kume, Oya Sayin, Semiha Terlemez, Esra Erdal, Nur Arslan. Adipokine levels and perilipin gene polymorphisms in obese Turkish adolescents with non- alcoholic fatty liver disease . Erciyes Med J. 2018 ; 43618. doi:10.5152/etd.20 18.0010.

Büyüköz M, Erdal E, Alsoy Altinkaya S. Nanofibrous gelatin scaffolds integrated with NGF-loaded alginate microspheres for brain tissue engineering. J Tissue Eng Regen Med. 2018 February; 12 (2): e707-e719. doi:10.1002/term.2353.

Aysim Gunes, Ezgi Bagirsakci, Evin Iscan, Gulcin Cakan-Akdogan, Umut Aykutlu, Serif Senturk, Gunes Ozhan, Esra Erdal, Deniz Nart, Funda Yilmaz Barbet, Nese Atabey. Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma. Oncotarget. 2018 ; 9 (96): 36849-36866. doi:10.18632/oncotarget.26402.

. Role of Albumin in growth inhibition in Hepatocellular Carcinoma.  Oncology. 2017 May; 93 (2): 136-142. doi:10.1159/000471807.

İşcan E, Güneş A, Korhan P, Yılmaz Y, Erdal E, Atabey N. The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells. J Cell Commun Signal. 2017 June; 11 (2): 155-166. doi:10.1007/s12079-016-0368-0.

Tokgöz Y, Işık IA, Akbari S, Kume T, Sayın O, Erdal E, Arslan N. Perilipin polymorphisms are risk factors for the development of obesity in adolescents? A case-control study. Lipids in health and disease. 2017 March; 16 (1): 52. doi:10.1186/s12944-017-0440-7.

Sebastian Ocklenburg, Ceren Barutçuoğlu, Adile Öniz Özgören, Murat Özgören, Esra Erdal, Dirk Moser, Judith Schmitz, Robert Kumsta and Onur Güntürkün . The Genetics of Asymmetry: Whole Exome Sequencing in a Consanguineous Turkish Family with an Overrepresentation of Left-Handedness. Symmetry. 2017 May; 9 (5): 66. doi:10.3390 /sym90 50066.

Firtina Karagonlar Z, Koç D, Şahin E, Avci ST, Yilmaz M, Atabey N, Erdal E. Effect of adipocyte-secreted factors on EpCAM+/CD133+ hepatic stem cell population.. Biochemical and biophysical research communications. 2016 January; 474 (3): 482-490. doi:10.1016/j.bbrc.2016.04.137.

Firtina Karagonlar Z, Koc D, Iscan E, Erdal E, Atabey N. Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells.. Cancer science. 2016 January; 107 (4): 407-16. doi:10.1111/cas.12891.

Yilmaz Y, Atabey N, Erdal E & Brian I. Carr. Platelets, Microenvironment and Hepatocellular Carcinoma. Biochemistry & Analytical Biochemistry. 2016 June; 5: 281. doi:10.4172/2161-1009.1000281.

Total: 12

Contact

Erdal Lab. on Stem Cell and Organoid Technologies

Group Leader

Esra ERDAL
esra.erdal@ibg.edu.tr
+90 232 299 41 00 (5031)
+9 02322994153