Refine
Has Fulltext
- yes (4)
Is part of the Bibliography
- yes (4)
Document Type
- Journal article (3)
- Doctoral Thesis (1)
Keywords
- Chlamydia (1)
- Endobrachyösophagus (1)
- Epithelial lineage (1)
- Esophageal adenocarcinoma (1)
- Esophageal disease (1)
- FT-IR spectroscopy (1)
- Gastroesophageal reflux (1)
- HPV (1)
- Intestinal metaplasia (1)
- Koordinationsisomerie (1)
- NDI-H (1)
- Organoid (1)
- Photoresponsives Verhalten (1)
- Retinoesäure (1)
- Retinoic acid (1)
- Selbstassemblierung (1)
- Supramolekulare Polymere (1)
- UV/Vis spectroscopy (1)
- cellular reprogramming (1)
- nanotube (1)
- nucleation-elongation model (1)
- supramolecular polymerization (1)
- transient absorption (1)
- π-Konjugierte Systeme (1)
Institute
EU-Project number / Contract (GA) number
- 715923 (1)
Coinfections with pathogenic microbes continually confront cervical mucosa, yet their implications in pathogenesis remain unclear. Lack of in-vitro models recapitulating cervical epithelium has been a bottleneck to study coinfections. Using patient-derived ectocervical organoids, we systematically modeled individual and coinfection dynamics of Human papillomavirus (HPV)16 E6E7 and Chlamydia, associated with carcinogenesis. The ectocervical stem cells were genetically manipulated to introduce E6E7 oncogenes to mimic HPV16 integration. Organoids from these stem cells develop the characteristics of precancerous lesions while retaining the self-renewal capacity and organize into mature stratified epithelium similar to healthy organoids. HPV16 E6E7 interferes with Chlamydia development and induces persistence. Unique transcriptional and post-translational responses induced by Chlamydia and HPV lead to distinct reprogramming of host cell processes. Strikingly, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair in the stem cells. Together, our study employing organoids demonstrates the hazard of multiple infections and the unique cellular microenvironment they create, potentially contributing to neoplastic progression.
A donor-acceptor-donor (D-A-D) type naphthalene-diimide (NDI-H) chromophore exhibits highly cooperative J-aggregation leading to nanotubular self-assembly and gelation in n-decane, as demonstrated by UV/Vis, FT-IR, photoluminescence and microscopy studies. Analysis of temperature-dependent UV/Vis spectra using the nucleation-elongation model and FT-IR data reveals the molecular origin of the cooperative nature of the self-assembly. The supramolecular polymerization is initiated by H-bonding up to a degree of polymerization similar to 20-25, which in a subsequent elongation step promotes J-aggregation in orthogonal direction leading to possibly a sheet-like structure that eventually produces nanotubes. Time-resolved fluorescence and absorption measurements demonstrate that such a tubular assembly enables very effective delocalization of excited states resulting in a remarkably prolonged excited state lifetime.
Hierin wird die inhärente geometrische Isomerie eines PtII Komplexes als neues Werkzeug zur Kontrolle von supramolekularen Assemblierungsprozessen ausgenutzt. Bestrahlung mit UV‐Licht sowie die sorgfältige Auswahl des verwendeten Lösungsmittels, der Temperatur und Konzentration führen zu einer regelbaren Koordinationsisomerie. Dies ermöglicht ein vollständig reversibles Schalten zwischen zwei definierten aggregierten Spezies (1D Fasern ↔ 2D Lamellen) mit unterschiedlichem photoresponsivem Verhalten. Unsere Erkenntnisse erweitern nicht nur die Reichweite von Koordinationsisomerie, sondern eröffnen auch aufregende Möglichkeiten zur Entwicklung neuartiger stimuliresponsiver Materialien.
Gastroesophageal junction (GEJ), demarcating the region where the distal esophagus meets with the proximal stomach region, is known for developing pathological conditions, including metaplasia and esophageal adenocarcinoma (EAC). It is essential to understand the mechanisms of developmental stages which lead to EAC since the incidence rate of EAC increased over 7-fold during the past four decades, and the overall five years survival rate is 18.4%. In most cases, patients are diagnosed in the advanced stage without prior symptoms. The main precursor for the development of EAC is a pre-malignant condition called Barrett's esophagus (BE). BE is the metaplastic condition where the multilayered squamous epithelium of the native esophagus is replaced by specialized single-layered columnar epithelium, which shows the molecular characteristics of the gastric as well as intestinal epithelium. The main risk factors for BE development include chronic gastro-esophageal acid reflux disease (GERD), altered microbiota, and altered retinoic acid signaling (RA). The cell of origin of BE is under debate due to a lack of clear evidence demonstrating the process of BE initiation. Here, I investigated how GEJ homeostasis is maintained in healthy tissue by stem cell regulatory morphogens, the role of vitamin A (RA signaling), and how its alteration contributes to BE development.
In the first part of my thesis, I showed the presence of two types of epithelial cells, the squamous type in the esophagus and the columnar type in the stomach region in the GEJ, using single-molecule RNA in situ hybridization (smRNA-ISH) and immunohistochemistry. Employing lineage tracing in the mouse model, I have demonstrated that the esophageal epithelial and stomach epithelial cells derived from two distinct epithelial stem cell lineages in the GEJ. The border between squamous and columnar epithelial cells in the Squamo-columnar junction (SCJ) of GEJ is regulated by opposing Wnt microenvironments. The regeneration of stomach columnar epithelial stem cells is maintained by Wnt activating signal from the stromal compartment while squamous epithelial stem cells of the esophagus are maintained by the Wnt inhibitory signals. I recapitulated the in vivo GEJ epithelial stem cell maintenance by using in vitro epithelial 3D organoid culture model. The growth and propagation of stomach columnar epithelial organoids depend on Wnt growth factors, while squamous epithelial organoids' development needs Wnt-deficient culture conditions.
Further, single-cell RNA sequence (scRNA-seq) analysis of organoid-derived epithelial cells revealed the non-canonical Wnt/ planar cell polarity (PCP) pathway involvement in regulating the squamous epithelial cells. In contrast, columnar stomach epithelial cells are regulated by the canonical Wnt/ beta-catenin and non-canonical Wnt/Ca2+ pathways. My data indicate that the SCJ epithelial cells that merge at the GEJ are regulated by opposing stromal Wnt factors and distinct Wnt pathway signaling in the epithelial cells.
In the second part of the thesis, I investigated the role of Vitamin A-derived bioactive compound RA on esophageal and stomach epithelial stem cells. In vitro treatment of esophageal and stomach, epithelial organoids with RA or its pharmacological inhibitor BMS 493 revealed that each cell type was regulated distinctly. I observed that enhanced RA promoted esophageal stem cell differentiation and loss of stratification, while RA inhibition led to enhanced stemness and regeneration of the esophagus stratified epithelium. As opposed to the esophagus, RA signaling is active in the stomach organoids, and inhibition of RA reduces the growth of stomach organoids. Global transcriptomic data and scRNA-seq data revealed that RA signaling induces dormancy phenotype in the esophageal cells. In contrast, the absence of RA in stomach epithelial cells induces the expression of genes associated with BE. Thus, spatially defined regulation of Wnt and RA signaling at GEJ is critical for healthy homeostasis, and its perturbation leads to disease development.