The microenvironment of pulmonary neuroepithelial bodies: a potential stem cell niche in the airway epithelium

Date: 17 December 2018

Venue: UAntwerp, Campus Drie Eiken, Building O, Auditorium O2 - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken)

Time: 4:30 PM - 6:30 PM

PhD candidate: Line Verckist

Principal investigator: Dirk Adriaensen, Inge Brouns

Short description: PhD defence Line Verckist - Department of Biomedical Sciences



Abstract

The neuroepithelial body (NEB) microenvironment (ME) consists of innervated groups of pulmonary neuroepithelial endocrine cells (PNECs), covered by so-called Clara-like cells (CLCs) in the intrapulmonary airway epithelium. Epithelial cells of conductive airways typically show a very low turnover rate in healthy postnatal lungs.

The first part of this thesis describes how dedicated laser microdissection (LMD) protocols could be combined with high-throughput PCR arrays for selective gene expression analysis of the NEB ME. More quantitative information about the expression of individual genes was derived from qPCR experiments and boosts our knowledge of the molecular characteristics of the mouse NEB ME.

Next, based on a single low-dose intratracheal lipopolysaccharide (LPS) instillation, a minimally invasive transient lung inflammation model was validated for inducing selective activation of a quiescent airway stem cell population, identified as CLCs, in the NEB ME of postnatal mouse lungs. The fact that CLCs can be activated from a silent to a dividing stem cell population, in the absence of identifiable damage to the airway epithelium and without the additional proliferation of PNECs, created new opportunities for unraveling the cellular mechanisms regulating silencing, proliferation and differentiation of this unique airway epithelial stem cell population.

Combining our optimized LMD protocols –to selectively isolate mRNA from NEB ME and control airway epithelium in both healthy control and LPS-challenged mice– with high-end gene expression analysis, allowed to characterize the NEB ME in postnatal mouse lungs as a quiescent stem cell niche that may be activated upon appropriate stimulation. Additionally, a number of pathways have been identified that appear to be involved in stem cell signaling within the NEB ME niche. For example, observations emphasized the potential involvement of bone morphogenetic protein (BMP) signaling in silencing cell proliferation in the non-activated stem cell niche of the healthy postnatal NEB ME.

In conclusion, our data strongly support the idea that CLCs should be regarded as real stem cells in the NEB ME niche but that they are silent in healthy postnatal airways. PNECs harbor a local pool of bioactive substances, including epithelial growth factors, and may cross-communicate with CLCs, but in our hands do not show proliferation following activation of the NEB ME. A better understanding of molecular mechanisms involved in the shift from quiescent to proliferating stem cells will be essential for developing effective therapies for inflammatory lung injury.



Link: https://www.uantwerpen.be/en/faculties/fbd/research/public-defence-of-a-phd/