Biology subjects

Eenjes, E.

Publications and source records attributed to Eenjes, E..

4 recordsLinked to original sources

bioRxiv2024

Regionalized cell and gene signatures govern oesophageal epithelial homeostasis

Regionalized disease prevalence is a common feature of the gastrointestinal tract. Herein, we employed regionally resolved Smart-seq3 single-cell sequencing, generating a comprehensive cell atlas of the adult mouse oesophagus. Characterizing the oesophageal axis, we unveil non-uniform distribution of epithelial basal cells, fibroblasts and immune cells. In addition, we reveal a position-dependent, but cell subpopulation-independent, transcriptional signature, collectively generating a regionalized oesophageal landscape. Combining in vivo models with organoid co-cultures, we demonstrate that proximal and distal basal progenitor cell states are functionally distinct. We find that proximal fibroblasts are more permissive for organoid growth compared to distal fibroblasts and that the immune cell profile is regionalized in two dimensions, where proximal-distal and epithelial-stromal gradients impact epithelial maintenance. Finally, we predict and verify how WNT-, BMP-, IGF-and NRG-signalling are differentially engaged along the oesophageal axis. We establish a cellular and transcriptional framework for understanding oesophageal regionalization, providing a functional basis for epithelial disease susceptibility.

cell biology↗

bioRxiv2024

Symmetrically fated progenitors dynamically accommodate tissue maintenance in the esophagus.

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 modelling 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.

cell biology↗

bioRxiv2022

Distinct roles for SOX2 and SOX21 in differentiation, distribution and maturation of pulmonary neuroendocrine cells

Pulmonary neuroendocrine (NE) cells represent a small population in the airway epithelium, but despite this, hyperplasia of NE cells is associated with several lung diseases, such as congenital diaphragmatic hernia and bronchopulmonary dysplasia. The molecular mechanisms causing the development of NE cell hyperplasia remains poorly understood. Previously, we showed that the SOX21 modulates the SOX2-initiated differentiation of epithelial cells in the airways (Eenjes, 2021). Here, we show that precursor NE cells start to develop in the SOX2+SOX21+ airway region and that SOX21 suppresses the differentiation of airway progenitors to precursor NE cells. During development, clusters of NE cells start to form and NE cells mature by expressing neuropeptide proteins, such as CGRP. Deficiency in SOX2 resulted in decreased clustering, while deficiency in SOX21 increased both the numbers of NE ASCL1+ precursor cells early in development, and the number of cell clusters at E18.5. In addition, at the end of gestation (E18.5), a number of NE cells in Sox2 heterozygous mice, did not yet express CGRP suggesting a delay in maturation. In conclusion, SOX2 and SOX21 function in the initiation, migration and maturation of NE cells.

developmental biology↗

bioRxiv2020

SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways

SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe SOX21 patterning of the proximal airway epithelium which coincides with high levels of SOX2. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. We show that loss of SOX21 results in increased differentiation of progenitor cells during murine lung development. SOX21 inhibits SOX2-induced differentiation by antagonizing SOX2 binding on different promotors. SOX21 remains expressed in adult tracheal epithelium and submucosal glands, where SOX21 modulates SOX2-induced differentiation in a similar fashion. Using fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+SOX21+ regionalization is conserved in human. Thus SOX21 modulates SOX2-initiated differentiation in extrapulmonary epithelial cells during development and regeneration after injury.

cell biology↗