Research Project: Karaciğer Fibrozisi ve Sirozun Şeffaflaştırma ve Floresan Mikroskopisi ile 3 Boyutlu Değerlendirilmesi
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Contributors
Funders
ID
TB.00353
Authors
Zeybel, Müjdat
Faculty Member
Publications
Investigating hepatic fibrosis heterogeneity by three-dimensional imaging in metabolic dysfunction-associated steatotic liver disease
(Nature Portfolio, 2025) Yiğit Alpdoğan, Buket; Özgönül, Ekin; Yaman, Ömer; Sipahioğlu, Tarık; Ulukan, Bürge; Taş, Yağmur Çetin; Morova, Berna; Uysallı, Yiğit; Tellioğlu, Gürkan; Atak, Dila; Özdemir, Yasemin Gürsoy; Karahüseyinoğlu, Serçin; Yurdaydın, Cihan; Akyıldız, Murat; Kiraz, Alper; Zeybel, Müjdat; Demirtaş, Elif; Ulukan, Bürge; Sipahioğlu, Tarık; Uysallı, Yiğit; Özgönül, Ekin; Yaman, Ömer; Aydin, Musa; Demirtas, Elif; Erkan, Mert; Sheth, Abhishek; Aithal, Guruprasad Padur; Kirimlioglu, Hale; Dayangac, Murat; Ferhanoglu, Onur; School of Medicine; Department of Physics; Graduate School of Health Sciences; Yes; Demirtaş, Elif; School of Medicine; College of Sciences
Although liver biopsy is a well-established technique to assess fibrosis it has several limitations, including invasive nature, semi-quantitative assessment methods, significant sampling and observer variability, making precise assessment of hepatic fibrosis challenging. Accurate and reliable modalities are crucial for clinical trials to characterize hepatic fibrosis monitorization effectively. We aimed to perform 3-dimensional imaging of optically transparent liver samples by light-sheet microscopy (LSM) to quantify extracellular matrix (ECM) proteins. Fifty-seven MASLD, thirty-eight chronic hepatitis patients and twelve healthy individuals were included. Liver tissues were cleared with a CLARITY method. 3D imaging of ECM was performed via the newly developed LSM. Collagen Proportionate Volume (CPV) and Elastin Proportionate Volume (EPV) values were calculated by analysis of over 200 sections per sample through morphometry. We have optimized a method which achieves transparency of liver tissues in advanced fibrotic stages of MASLD and optimized non-destructive slide-free fibrosis pathology of whole fresh and FFPE liver biopsy samples. Cut-off values for CPV and EPV were established for fibrotic stages. CPV and EPV analysis showed a considerable optical section heterogeneity resulting in a fibrosis stage of variance within the sample. Volumetric image analysis for fibrosis staging revealed that only 44% and 47% of optical sections would be staged the same for F3 and F4, respectively. For the first time, our findings demonstrate a novel method of analyzing 3D digital pathology of liver fibrosis using in-house LSM. Volumetric imaging of whole liver biopsy samples showed that fibrosis heterogeneity occurs even in different sections.
Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies
(Cell Press, 2025) Atak, Dila; Ulukan, Bürge; Yurdaydın, Cihan; Akyıldız, Murat; Zeybel, Müjdat; Demirtaş, Elif; Peltek, İbrahim Batuhan; Saka, Burcu; Yiğit Alpdoğan, Buket; Sipahioğlu, Tarık; Ulukan, Bürge; Sipahioğlu, Tarık; Yang,Hong; Yuan,Meng; Li,Mengzhen; Altay,Ozlem; Alvez,MariaBueno; Meng,Lingqi; Yuksel,Bayram; Turkez,Hasan; Kirimlioglu,Hale; Dayangac,Murat; Uhlen,Mathias; Boren,Jan; Zhang,Cheng; Mardinoglu,Adil; KUH (Koç University Hospital); School of Medicine; Yes; Demirtaş, Elif; KUH (KOÇ UNIVERSITY HOSPITAL); SCHOOL OF MEDICINE; Peltek, İbrahim Batuhan
Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81-0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78- 0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.
