| 1. |
- Grommisch, David, et al.
(författare)
-
Defining the contribution of Troy-positive progenitor cells to the mouse esophageal epithelium
- 2024
-
Ingår i: Developmental Cell. - 1534-5807 .- 1878-1551. ; 59:10, s. 6-1283
-
Tidskriftsartikel (refereegranskat)abstract
- Progenitor cells adapt their behavior in response to tissue demands. However, the molecular mechanisms controlling esophageal progenitor decisions remain largely unknown. Here, we demonstrate the presence of a Troy (Tnfrsf19)-expressing progenitor subpopulation localized to defined regions along the mouse esophageal axis. Lineage tracing and mathematical modeling demonstrate that Troy-positive progenitor cells are prone to undergoing symmetrical fate choices and contribute to esophageal tissue homeostasis long term. Functionally, TROY inhibits progenitor proliferation and enables commitment to differentiation without affecting fate symmetry. Whereas Troy expression is stable during esophageal homeostasis, progenitor cells downregulate Troy in response to tissue stress, enabling proliferative expansion of basal cells refractory to differentiation and reestablishment of tissue homeostasis. Our results demonstrate functional, spatially restricted progenitor heterogeneity in the esophageal epithelium and identify how dynamic regulation of Troy coordinates tissue generation.
|
|
| 2. |
- Grommisch, David
(författare)
-
Not just a pipe's dream : plumbing the contribution of cell diversity to oesophageal homeostasis
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epithelial barrier tissues like the skin, intestine, and oesophagus form a physical barrier that protects our body from external threats. To accurately fulfil their function, epithelial barriers are subject to constant epithelial cell renewal throughout our lifespan. Recurrent tissue turnover requires the precise control of epithelial cell proliferation and differentiation to maintain homeostasis and health. Adult tissue stem cells residing in epithelial barriers are of pivotal importance for tissue homeostasis and repair. The stem cell niche, composed of a variety of cells, mechanical and chemical elements, provides decisive signalling cues that influence stem cell behaviour and fate. The major part of this thesis investigates behaviour of the mouse oesophageal epithelial progenitor cell and sets out to uncover and characterise the contribution of cellular diversity to oesophageal homeostasis. In paper III, we demonstrated that a subpopulation of oesophageal progenitor cells expressed Tnfrsf19 (Troy) and contributed long-term to oesophageal homeostasis. Using lineage tracing in combination with mathematical modelling we proposed that Troy progenitor cell fate is predominantly symmetrical. In addition, functional TROY knockout in vivo suggested that TROY regulates progenitor proliferation and facilitates differentiation. Thus, TROY might be involved in context dependent cellular decision making processes providing a basis for behavioural progenitor heterogeneity. In paper IV, we characterise regional oesophageal cell composition utilising single cell RNA sequencing. Combining cell-cell communication inference and organoid culture we reveal regionally diverse contributions of fibroblasts and immune cells as well as signalling pathways such as BMP and IGF that differently influence epithelial cell behaviour. In paper II, we developed an organoid co-culture system of oesophageal epithelial cells and fibroblasts that allows for detailed functional investigations of cell-cell communication in vitro. The generation of the stratified squamous epithelium of the skin is governed by intricate and interwoven processes of proliferation, cell cycle exit, differentiation, and stratification. In paper I, we probed the function of ID1 in epidermal development and demonstrated ID1 binding to the transcription factor TCF3. We propose that ID1-CEBPA crosstalk regulates epidermal cell fate decision within a ID1-TCF3-CEBPA axis. The work provided within this thesis demonstrates molecular mechanisms and signalling cues that impinge on epithelial cell behaviour during homeostasis and development.
|
|
| 3. |
- Lund, Harald, et al.
(författare)
-
Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
- 2018
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a– microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.
|
|
