Calà, Giuseppe;
(2025)
Prenatal derivation of epithelial organoids from human fetal fluids to model development and disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Tissue stem cell-derived fetal organoids represent a powerful in vitro model of developing tissues. However, isolation of human fetal tissue-specific stem cells and derivation of primary organoids is restricted to samples obtained after termination of pregnancy. This limits the study of fetal development and congenital diseases. To address this gap, this research explored the development of novel fetal stem cell-derived organoid models. In this context, fetal fluids offer a minimally invasive alternative to access fetal cells during human development. In particular, the amniotic fluid (AF) is a source of cells shed by multiple developing organs. Through the generation of the first atlas of unperturbed AF cellular content, viable epithelial stem/progenitor cells of fetal gastrointestinal, renal, and pulmonary origin were identified. When 3D cultured, these cells formed clonal epithelial organoids, manifesting small intestine, kidney tubule, and lung identity. AF-derived organoids (AFOs) exhibit transcriptomic, protein expression and functional features of their fetal tissue of origin, representing the first example of a minimally invasive approach to isolate primary fetal organoids from continuing pregnancies. Furthermore, I established lung organoids from amniotic and tracheal fluid cells of congenital diaphragmatic hernia (CDH) fetuses. CDH lung organoids recapitulated some features of hypoplastic lungs and reflected the fetal surgical intervention, indicating the potential of fetal fluid-derived organoids for disease modelling. AFOs are derived during ongoing pregnancies without requiring tissue biopsies or reprogramming, and represent a regenerative medicine tool autologous to the fetus. Additionally, AFOs enable the study of late-stage development, which has been previously challenging to access. This PhD research pioneers the generation and characterisation of primary epithelial organoids derived from human fetal fluids, highlighting their potential for modelling developing epithelia and congenital disease.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Prenatal derivation of epithelial organoids from human fetal fluids to model development and disease |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203383 |
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