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.

Selected Publications

Tokgöz Y, Erdur CB, Akbari S, Kume T, Sayin O, Terlemez S, Erdal E, Arslan N. 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.

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.

Kose E, Guzel O, Arslan. Analysis of hematological parameters in patients treated with ketogenic diet due to drug-resistant epilepsy. Neurol Sci.. 2018 Jan ; 39 (1): 85-89. doi:10.1007/s10072-017-3152-x.

Yıldırım Ö, Demircan T, Tüfekçi Ö, Kızılca Ö, Kuyum P, Kır M, Abacı A, Ünal N, Arslan N, Böber E, Yılmaz Ş, Ören H. Anemia and its effect on cardiovascular findings in obese adolescents . Turk J Hematol. 2018 Aug ; 35 (3): 192-196. doi:10.4274/tjh.2018.0103 .

Pinto A, Adams S, Ahring K, Allen H, Almeida MF, Garcia-Arenas D, Arslan N, Assoun M, Atik Altınok Y, Barrio-Carreras D, Belanger Quintana A, Bernabei SM, Bontemps C, Boyle F, Bruni G, Bueno-Delgado M, Caine G, Carvalho R, Chrobot A, Chyż K, Cochrane B, Correia C, Corthouts K, Daly A, De Leo S, Desloovere A, De Meyer A, De Theux A, Didycz B, Dijsselhof ME, Dokoupil K, Drabik J, Dunlop C, Eberle-Pelloth W, Eftring K, Ekengren J, Errekalde I, Evans S, Foucart A, Fokkema L, François L, French M, Forssell E, Gingell C, Gonçalves C, Gökmen Özel H, Grimsley A, Gugelmo G, Gyüre E, Heller C, Hensler R, Jardim I, Joost C, Jörg-Streller M, Jouault C, Jung A, Kanthe M, Koç N, Kok IL, Kozanoğlu T, Kumru B, Lang F, Lang K, Liegeois I, Liguori A, Lilje R, Ļubina O, Manta-Vogli P, Mayr D, Meneses C, Newby C, Meyer U, Mexia S, Nicol C, Och U, Olivas SM, Pedrón-Giner C, Pereira R, Plutowska-Hoffmann K, Purves J, Re Dionigi A, Reinson K, Robert M, Robertson L, Rocha JC, Rohde C, Rosenbaum-Fabian S, Rossi A, Ruiz M, Saligova J, Gutiérrez-Sánchez A, Schlune A, Schulpis K, Serrano-Nieto J, Skarpalezou A, Skeath R, Slabbert A, Straczek K, Giżewska M, Terry A, Thom R, Tooke A, Tuokkola J, van Dam E, van den Hurk TAM, van der Ploeg EMC, Vande Kerckhove K, Van Driessche M, van Wegberg AMJ, van Wyk K, Vasconcelos C, Velez García V, Wildgoose J, Winkler T, Żółkowska J, Zuvadelli J, MacDonald A.. Early feeding practices in infants with phenylketonuria across Europe. Mol Genet Metab Rep . 2018 Aug ; 16 82-89. doi:10.1016/j.ymgmr.2018.07.008 .

Cubukcu D, Guzel O, Arslan N. Effect of ketogenic diet on motor functions and daily living activities of children with multidrug-resistant epilepsy: A prospective study. Journal of Child Neurolgy. 2018 ; 33 (11): 718-723. doi:10.1177/0883073818786558.

Omer F., Beser M.D., Fugen Cullu Cokugras M.D., Tulay Erkan M.D., Tufan Kutlu M.D., Rasit V., Yagci M.D., TUHAMAR Study Group. Evaluation of malnutrition development risk in hospitalized children . Nutrition. 2018 Apr ; 48 40-47. doi:10.1016/j.nut.2017.10.020 .

Kose E, Kuyum P, Aksoy B, Häberle J, Arslan N, Ozturk Y. First report of carglumic acid in a patient with citrullinemia type 1 (argininosuccinate synthetase deficiency). J Clin Pharm Ther. 2018 Feb ; 43 (1): 124-128. doi:10.1111/jcpt.12593..

Semra Gürsoy, Esra Ataman, Özlem Giray Bozkaya, Engin Köse, Müge Ayanoğlu, Ayşe İpek Polat, Nur Arslan, Semra Hız Kurul, Derya Erçal. Identification of the largest homozygous glycine decarboxylase gene deletion in a Turkish infant. Pediatrics and Neonatology. 2018 Dec ; 59 (6): 632-633. doi:10.1016/j.pedneo.2018.01.011.

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 Feb ; 12 (2): e707-e719. doi:10.1002/term.2353.

Işık S, Karaman M, Micili SÇ, Çağlayan-Sözmen Ş, Bağrıyanık HA, Arıkan-Ayyıldız Z, Uzuner N, Karaman Ö. Sinomenine ameliorates the airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in a murine model of chronic asthma. Allergologia et immunopathologia. 2018 Feb ; 46 (1): 67-75. doi:10.1016/j.aller.2017.05.004.

Kose E, Aksoy B, Kuyum P, Tuncer N, Ozturk Y. The effects of breastfeeding in infants with phenylketonuria. J Pediatr Nurs . 2018 Feb ; 38 27-32. doi:10.1016/j.pedn.2017.10.009.

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: https://doi.org/10.18632/oncotarget.26402.

Kose E, Arslan N. Vitamin/mineral and micronutrient status in patients with classical phenylketonuria. Clinical Nutrition. 2018 Feb doi:https://doi.org/10.1016/j.clnu.2018.01.034.

Bağırsakçı E, Şahin E, Atabey N, Erdal E, Guerra V and Carr BI. 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 Jun ; 11 (2): 155-166. doi:10.1007/s12079-016-0368-0.

Engin Köse, Uluc Yis, Semra Hiz, Nur Arslan. A novel mutation in the glycine decarboxylase gene in patient with non-ketotic hyperglycinemia. Neurosciences. 2017 Apr ; 22 (2): 131-133. doi:10.17712/nsj.2017.2.20160468.

İmge KUNTER, Emine KANDEMİŞ, Hani ALOTAİBİ, Tülay CANDA, Esra ERDAL BAĞRIYANIK. Alteration in the subcellular location of the inhibitor of growth protein p33(ING1b) in estrogen receptor alpha positive breast carcinoma cells. Turkish Journal of Biology. 2017 ; 41 (1): 105-112. doi:10.3906/biy-1602-95 .

Işık S, Karaman M, Çilaker Micili S, Çağlayan-Sözmen Ş, Bağrıyanık HA, Arıkan-Ayyıldız Z, Uzuner N, Karaman Ö. Beneficial effects of ursodeoxycholic acid via inhibition of airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in murine model of chronic asthma.. Allergologia et immunopathologia. 2017 Jul ; 45 (4): 339-349. doi:10.1016/j.aller.2016.12.003.

Köse E, Güzel O, Demir K, Arslan N. Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy. Journal of Pediatric Endocrinology and Metabolism. 2017 Apr ; 30 (4): 411-416. doi:10.1515/jpem-2016-0281 .

Işık S, Uzuner N, Karaman M, Karaman Ö, Kıray M, Kozanoğlu İ, Alper Bağrıyanık H, Arıkan-Ayyıldız Z, Kartal Yandım M, Baran Y. Effects of Intraperitoneal Injection of Allogeneic Bone Marrow-derived Mesenchymal Stem Cells on Bronchiolitis Obliterans in Mice Model. Iranian journal of allergy, asthma, and immunology. 2017 Jun ; 16 (3): 205-218.

Engin Kose, Ozlem Unal, Selda Bulbul, Mehmet Gunduz, Johannes Häberle, Nur Arslan. Identification of three novel mutations in fourteen patients with citrullinemia type 1. Clin Biochem.. 2017 Aug ; 50 (12): 686-689. doi:10.1016/j.clinbiochem.2017.01.011.

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 Mar ; 16 (1): 52. doi:10.1186/s12944-017-0440-7.

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 Mar ; 16 (1): 52. doi:10.1186/s12944-017-0440-7.

Arslan N, Köse E, Güzel O. The Effect of Ketogenic Diet on Serum Selenium Levels in Patients with Intractable Epilepsy. Biol Trace Elem Res.. 2017 Jul ; 178 (1): 1-6. doi:10.1007/s12011-016-0897-7.

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.

Contact

Erdal Lab. on Stem Cell and Organoid Technologies

Prof.Dr. Esra ERDAL
esra.erdal@ibg.edu.tr
+90 232 299 41 00 (5031)
+90 232 299 41 53