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Constant inhibition of local BMP signaling contributes to recovery of mucociliary epithelium from Tracheobronchopathia Osteochondroplastica (TO)-associated pathophysiology via basal cell restoration

ABSTRACT: Constant inhibition of local BMP signaling contributes to recovery of mucociliary epithelium from Tracheobronchopathia Osteochondroplastica (TO)-associated pathophysiology via basal cell restoration

PROVIDER: PRJNA641925 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15904883_1.fastq.gz	Fastqsanger.gz
	SRR15904883_2.fastq.gz	Fastqsanger.gz
	SRR15904884_1.fastq.gz	Fastqsanger.gz
	SRR15904884_2.fastq.gz	Fastqsanger.gz
	SRR15904885_1.fastq.gz	Fastqsanger.gz

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Constant inhibition of local BMP signaling contributes to recovery of mucociliary epithelium from Tracheobronchopathia Osteochondroplastica (TO)-associated pathophysiology via basal cell restoration

Project description:Tracheobronchial basal cells have been found to undergo persistent functional changes, via acting as a local repository for BMP signaling elements, thereby play a driven role in TO pathogenesis. Although it would be unlikely to fundamentally correct cell fate alteration, because of epigenetic changes occurred, partial restoration of epithelial physiology may be achieved by braking self-amplifying BMP signaling loop. To investigate the effect of BMP inhibition on TO-derived basal cells, ALI structures derived from routine differentiation without Noggin treatment and modified differentiation with constant BMP inhibition were subjected to RNA-sequencing. While a differentiation pattern of 3538 genes up-regulated and 2109 genes down-regulated (>2-fold or <-2-fold, p<0.05) upon routine differentiation of a typical TO-derived pedigree, differentiation in the presence of BMP inhibition resulted in an up-regulation of 4101 genes and down-regulation of 2337 genes (equivalent cutoff as above). Among those 1554 genes with significantly increased expression on ALI under BMP inhibition, a major enrichment shown up in categories related to cilium assembly and function, and an up-turned Smoothened signaling were detected. In contrast, 482 genes with decreased expression under BMP inhibition were mainly fallen into categories related to biomineral tissue development. These data suggest that constant repression of local BMP signaling has a favorable effect, to some extent, on functional rescue of pathological basal cells.

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Project description:The regeneration of the airway mucociliary epithelium involves several sequential events including migration, proliferation, polarization and final differentiation (i.e ciliogenesis). The airway mucociliary epithelium is consituted of three main cell types : ciliated cells, secretory cells and basal cells. We used microRNA microrrays to investigate the signature of microRNA during the four step of regeneration of the airway epithelium. Four time points (ALI-D0, ALI-D7, ALI-D14, ALI-D21) of regeneration of the airway epithelium for 3 donors.

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Project description:Foxi1 is a master regulator of ionocytes (ISCs / INCs) across species and organs. Two subtypes of ISCs exist, and both - and -ISCs regulate pH- and ion-homeostasis in epithelia. Gain and loss of FOXI1 function are associated with human diseases, including Pendred syndrome, male infertility, renal acidosis and cancers. Foxi1 was predominantly studied in the context of ISC specification, however, reports indicate additional functions in early and ectodermal development. Here, we re-investigated the functions of Foxi1 in Xenopus laevis embryonic mucociliary epidermis development and found a novel function for Foxi1 in the generation of Notch-ligand expressing mucociliary multipotent progenitors (MPPs). We demonstrate that Foxi1 has multiple concentration-dependent functions: At low levels, Foxi1 maintains ectodermal competence in MPPs through transcriptional and epigenetic mechanisms, while at high levels, Foxi1 induces a multi-step process of ISC specification and differentiation in cooperation with Ubp1 and Dmrt2. We further describe how foxi1 expression is affected through auto- and Notch-regulation, and how this developmental program affects mucociliary patterning. Together, we reveal novel functions for Foxi1 in Xenopus mucociliary epidermis formation, relevant to our understanding of vertebrate development and human disease.

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