Refining the neutral competition model to understand stem-cell mediated homeostasis in the Drosophila midgut

Fernandez Garcia, Cristina 2023. Refining the neutral competition model to understand stem-cell mediated homeostasis in the Drosophila midgut. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Summary Intestinal Stem Cells (ISCs) maintain intestinal tissue homeostasis in mammals and Drosophila by dividing and differentiating into various types to replenish cells in a tissue constantly facing challenges like mechanical abrasion or pH shifts. In Drosophila, tissue turnover involves the neutral competition of symmetrically dividing stem cells. ISCs compete for niche occupancy without inherent advantages, leading to stochastic expansion or loss of specific lineages. However, this model of neutral competition assumes that ISCs have uniform division rate, which is challenged by experimental observations. To address this, we proposed the quiescence-division switch model: two states for ISCs under homeostatic conditions, a static state with no division and a dynamic state where all ISCs in the same compartment divide at the same rate, so areas of fast and slow turnover can coexist. We proposed heat shock (HS) could trigger the switch from these states. Immunofluorescence analysis on cell cycle markers showed increased mitotic activity after HS, supporting this switch, with no increase in cell loss associated. We employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene clusters correlating with this response. Enterocytes demonstrated upregulated genes for DNA repair and downregulated genes for metabolism and growth. An unannotated cluster, likely related to progenitor cells, showed upregulation of cell cycle-related genes. Homeostasis also includes ISC differentiation. Next, we focused on basic helix-loop-helix (bHLH) transcription factors, specifically Daughterless (Da) and Scute (Sc), which are essential for enteroendocrine (EE) cell differentiation. Our results support a 'Sc Threshold Scenario,' where a critical concentration of Da:Sc heterodimers initiates pre-EE cell differentiation. Finally, we proposed a novel gene expression system for studying the quiescence-division model, independent of temperature and compatible with Gal4-UAS, which makes use of trimethoprim (TMP) to induce gene expression. We studied TMP's safety and efficacy in the Drosophila midgut, which showed no harmful effects.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	27 June 2024
Last Modified:	27 Jun 2024 13:21
URI:	https://orca.cardiff.ac.uk/id/eprint/170143

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