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Dirice, Ercument

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Dirice

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Ercument

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Dirice, Ercument

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2014 - 20163

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Author's Publications: search.filters.isAuthorOfPublication.57d9646f-5309-433e-974a-5b5a86702c92

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    Comparable Generation of Activin-Induced Definitive Endoderm via Additive Wnt or BMP Signaling in Absence of Serum
    (Elsevier, 2014) Teo, Adrian Kee Keong; Valdez, Ivan Achel; Dirice, Ercument; Kulkarni, Rohit N.
    Summary There is considerable interest in differentiating human pluripotent stem cells (hPSCs) into definitive endoderm (DE) and pancreatic cells for in vitro disease modeling and cell replacement therapy. Numerous protocols use fetal bovine serum, which contains poorly defined factors to induce DE formation. Here, we compared Wnt and BMP in their ability to cooperate with Activin signaling to promote DE formation in a chemically defined medium. Varying concentrations of WNT3A, glycogen synthase kinase (GSK)-3 inhibitors CHIR99021 and 6-bromoindirubin-3′-oxime (BIO), and BMP4 could independently co-operate with Activin to effectively induce DE formation even in the absence of serum. Overall, CHIR99021 is favored due to its cost effectiveness. Surprisingly, WNT3A was ineffective in suppressing E-CADHERIN/CDH1 and pluripotency factor gene expression unlike GSK-3 inhibitors or BMP4. Our findings indicate that both Wnt and BMP effectively synergize with Activin signaling to generate DE from hPSCs, although WNT3A requires additional factors to suppress the pluripotency program inherent in hPSCs.
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    Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia
    (Elsevier, 2016) Teo, Adrian Kee Keong; Lau, Hwee Hui; Valdez, Ivan Achel; Dirice, Ercument; Tjora, Erling; Raeder, Helge; Kulkarni, Rohit N.
    Summary Patients with an HNF1BS148L/+ mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human-induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1BS148L/+ mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1BS148L/+ but not wild-type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1BS148L/+ protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.
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    Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes
    (Cell Press, 2015-08-04) Bhatt, Schweta; Gupta, Manoj; Khamaisi, Mogher; Martinez, Rachael; Gritsenko, MA; Wagner, Bridget K.; Guye, Patrick; Busskamp, Volker; Shirakawa, Jun; Wu, Gongxiong; Liew, CW; Clauss, Therese; Valdez, Ivan; El Ouaamari, Abdelfattah; Dirice, Ercument; Takatani, Tomozumi; Keenan, Hillary A.; Smith, RD; Church, George; Weiss, Ron; Wagers, Amy; Qian, Wei-Jun; King, George; Kulkarni, Rohit
    The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D(disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist −C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist −C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.