Improving pancreatic lineage commitment of human pluripotent stem cells in terms of pancreas development and disease modelling
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Date
2025-04-17
Authors
Merz, Sarah
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Dissertation
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Abstract
Pancreatic lineage differentiation has predominantly focused on driving the generation of functional β-cells, given their significance in diabetes research and therapy. However, for comprehensive disease modeling and a better understanding of the entire pancreas, including its interactions and functions, it is likewise crucial to generate cells of the exocrine compartment. The objective of the first part of this doctoral thesis was to optimize the differentiation of hESCs toward the pancreatic lineage. This included a detailed characterization of pancreatic progenitors to understand their marker profiles and cellular heterogeneity, and to direct their further specification into endocrine and exocrine lineages. Additionally, this work aimed to implement an ex vivo culture system to achieve robust, long-term maturation of pancreatic cells.
The second part of the thesis aimed to utilize the optimized differentiation system for modelling monogenic neonatal diabetes (Figure 2). In this specific case, a child diagnosed with severe neonatal diabetes, and his family history of T2D, served as basis for this study. This part of the doctoral thesis involved integrating gene engineering with pancreatic differentiation, various sequencing approaches and functionality assays to decipher the underlying disease mechanisms. A key focus was to elucidate the regulatory role of a non-coding region on ONECUT1 expression and its impact on islet development.
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Faculties
Medizinische Fakultät
Institutions
UKU. Institut für Molekulare Onkologie und Stammzellbiologie
Zentralinstitut für Biomedizinische Technik (ZIBMT)
Zentralinstitut für Biomedizinische Technik (ZIBMT)
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DFG Project uulm
EU Project THU
Other projects THU
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CC BY 4.0 International
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Melzer MK, Breunig M, Lopatta P, Hohwieler M, Merz S, Azoitei A, Günes C, Bolenz C, and Kleger A, Protocol to use de-epithelialized porcine urinary bladder as a tissue scaffold for propagation of pancreatic cells. STAR protocols, 2022. 3(4): p. 101869. doi: https://doi.org/10.1016/j.xpro.2022.101869
Merz S, Breunig M, Melzer MK, Heller S, Wiedenmann S, Seufferlein T, Meier M, Krüger J, Mulaw MA, and Hohwieler M, Single-cell profiling of GP2-enriched pancreatic progenitors to simultaneously create acinar, ductal, and endocrine organoids. Theranostics, 2023. 13(6): p. 1949. https://www.thno.org/v13p1949
Merz S, Senée V, Philippi A, Oswald F, Shaigan M, Führer M, Drewes C, Allgöwer C, Öllinger R, Heni M, Boland A, Deleuze J-F, Birkhofer F, Gusmao EG, Wagner M, Hohwieler M, Breunig M, Rad R, Siebert R, Messerer DAC, Costa IG, Alvarez F, Julier C, Kleger A, and Heller S, A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes. Cell Reports, 2024. 43(11). DOI: 10.1016/j.celrep.2024.114853 https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01204-X
Merz S, Breunig M, Melzer MK, Heller S, Wiedenmann S, Seufferlein T, Meier M, Krüger J, Mulaw MA, and Hohwieler M, Single-cell profiling of GP2-enriched pancreatic progenitors to simultaneously create acinar, ductal, and endocrine organoids. Theranostics, 2023. 13(6): p. 1949. https://www.thno.org/v13p1949
Merz S, Senée V, Philippi A, Oswald F, Shaigan M, Führer M, Drewes C, Allgöwer C, Öllinger R, Heni M, Boland A, Deleuze J-F, Birkhofer F, Gusmao EG, Wagner M, Hohwieler M, Breunig M, Rad R, Siebert R, Messerer DAC, Costa IG, Alvarez F, Julier C, Kleger A, and Heller S, A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes. Cell Reports, 2024. 43(11). DOI: 10.1016/j.celrep.2024.114853 https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01204-X
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Keywords
Human pluripotent stem cells, Diabetes mellitus, Bauchspeicheldrüse, Induzierte pluripotente Stammzelle, Diabetes mellitus, Pluripotent stem cells, Pancreas, DDC 610 / Medicine & health