YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands
<p>In the gastrointestinal tract, tissue regeneration relies on stem cells localised within specific niches. The factors determining this spatial restriction remain unknown. Coordinated activation of signalling pathways is essential during organogenesis and extends to adult tissue for the main...
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| Format: | Thesis |
| Language: | English |
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2024
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| _version_ | 1824458984302575616 |
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| author | Zagami, C |
| author2 | Boccellato, F |
| author_facet | Boccellato, F Zagami, C |
| author_sort | Zagami, C |
| collection | OXFORD |
| description | <p>In the gastrointestinal tract, tissue regeneration relies on stem cells localised within specific niches. The factors determining this spatial restriction remain unknown. Coordinated activation of signalling pathways is essential during organogenesis and extends to adult tissue for the maintenance of homeostasis. Although the Wnt/β-catenin signalling pathway is known to be crucial for regeneration, it is unclear why only cells within a specific niche actively regenerate, while others do not.</p>
<p>The human stomach is organised into epithelial invaginations called gastric glands. While tissue damage can trigger regeneration at the gland base, in healthy conditions, stem cell activity is restricted to an anatomical niche called the isthmus. To investigate the mechanisms behind this spatial restriction, we analysed the spatial distribution of gene expression in the healthy human stomach using NanoString GeoMx spatial transcriptomics to predict the local activity of signalling pathways.</p>
<p>Key signalling molecules identified as spatially variable were validated in vitro using healthy human stomach 3D stem cell-driven cultures. By manipulating the culture environment, we discovered that stem cell proliferation in the isthmus is maintained by active Wnt/β-catenin signalling, whereas DKK1 inhibits β-catenin activity and regeneration at the base. Interestingly, DKK1 expression was found to spatially correlate with and be regulated by YAP, a key coactivator acting via binding to the TEAD transcription factor of the mechano-sensing Hippo pathway.</p>
<p>Studying tissue homeostasis in humans is challenging, as genetic tracing tools used in animal models are unavailable. By combining the analysis of spatial transcriptomics data with the validation in 3D stem cell-driven models, we were able to investigate human gastric tissue homeostasis. We found that the YAP-DKK1 axis restricts regeneration to the isthmus of the human stomach by inhibiting the Wnt/β-catenin signalling.</p>
<p>Future studies should explore how the dysregulation of regeneration observed in stomach pathological conditions may derive from altered perception of microenvironmental mechanical forces.</p> |
| first_indexed | 2025-02-19T04:34:34Z |
| format | Thesis |
| id | oxford-uuid:4dd0c094-6206-4a13-a8b7-fce7f7fd8fc9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:34:34Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:4dd0c094-6206-4a13-a8b7-fce7f7fd8fc92025-01-27T08:55:09ZYAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glandsThesishttp://purl.org/coar/resource_type/c_db06uuid:4dd0c094-6206-4a13-a8b7-fce7f7fd8fc9This thesis postulates that YAP-DKK1 interaction restricts regenerative cellular activity to the isthmus of the stomach gastric gland, by inhibiting Wnt/β-catenin signalling pathway.EnglishHyrax Deposit2024Zagami, CBoccellato, FGoding, C<p>In the gastrointestinal tract, tissue regeneration relies on stem cells localised within specific niches. The factors determining this spatial restriction remain unknown. Coordinated activation of signalling pathways is essential during organogenesis and extends to adult tissue for the maintenance of homeostasis. Although the Wnt/β-catenin signalling pathway is known to be crucial for regeneration, it is unclear why only cells within a specific niche actively regenerate, while others do not.</p> <p>The human stomach is organised into epithelial invaginations called gastric glands. While tissue damage can trigger regeneration at the gland base, in healthy conditions, stem cell activity is restricted to an anatomical niche called the isthmus. To investigate the mechanisms behind this spatial restriction, we analysed the spatial distribution of gene expression in the healthy human stomach using NanoString GeoMx spatial transcriptomics to predict the local activity of signalling pathways.</p> <p>Key signalling molecules identified as spatially variable were validated in vitro using healthy human stomach 3D stem cell-driven cultures. By manipulating the culture environment, we discovered that stem cell proliferation in the isthmus is maintained by active Wnt/β-catenin signalling, whereas DKK1 inhibits β-catenin activity and regeneration at the base. Interestingly, DKK1 expression was found to spatially correlate with and be regulated by YAP, a key coactivator acting via binding to the TEAD transcription factor of the mechano-sensing Hippo pathway.</p> <p>Studying tissue homeostasis in humans is challenging, as genetic tracing tools used in animal models are unavailable. By combining the analysis of spatial transcriptomics data with the validation in 3D stem cell-driven models, we were able to investigate human gastric tissue homeostasis. We found that the YAP-DKK1 axis restricts regeneration to the isthmus of the human stomach by inhibiting the Wnt/β-catenin signalling.</p> <p>Future studies should explore how the dysregulation of regeneration observed in stomach pathological conditions may derive from altered perception of microenvironmental mechanical forces.</p> |
| spellingShingle | This thesis postulates that YAP-DKK1 interaction restricts regenerative cellular activity to the isthmus of the stomach gastric gland, by inhibiting Wnt/β-catenin signalling pathway. Zagami, C YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands |
| title | YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands |
| title_full | YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands |
| title_fullStr | YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands |
| title_full_unstemmed | YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands |
| title_short | YAP-DKK1 axis restricts regeneration to the isthmus of the human gastric glands |
| title_sort | yap dkk1 axis restricts regeneration to the isthmus of the human gastric glands |
| topic | This thesis postulates that YAP-DKK1 interaction restricts regenerative cellular activity to the isthmus of the stomach gastric gland, by inhibiting Wnt/β-catenin signalling pathway. |
| work_keys_str_mv | AT zagamic yapdkk1axisrestrictsregenerationtotheisthmusofthehumangastricglands |