Integrated mRNA and microRNA transcriptome profiling during differentiation of human nasal polyp epithelium reveals an altered ciliogenesis

Abstract

Background: Human adult basal stem/progenitor cells (BSCs) obtained from chronic rhinosinusitis with nasal polyps (CRSwNP) when differentiated in an air-liquid interface (ALI) usually provide a pseudostratified airway epithelium with similar abnormalities than original in vivo phenotype. However, the intrinsic mechanisms regulating this complex process are not well defined and their understanding could offer potential new therapies for CRSwNP (incurable disease). Methods: We performed a transcriptome-wide analysis during in vitro mucociliary differentiation of human adult BSCs from CRSwNP, compared to those isolated from control nasal mucosa (control-NM), in order to identify which key mRNA and microR-NAs are regulating this complex process in pathological and healthy conditions. Results: A number of genes, miRs, biological processes, and pathways were identified during mucociliary differentiation of both CRSwNP and control-NM epithelia, and notably, we have demonstrated for the first time that genetic transcriptional program responsible of ciliogenesis and cilia function is significantly impaired in CRSwNP epithelium, presumably produced by an altered expression of microRNAs, particularly of those miRs belonging to mir-34 and mi-449 families. Conclusions: This study provides for the first time a novel insight into the molecular basis of sinonasal mucociliary differentiation, demonstrating that transcriptome related to ciliogenesis and cilia function is significantly impaired during differentiation of CRSwNP epithelium due to an altered expression of microRNAs.

Spotlight on microRNAs in allergy and asthma

“…The importance of miRNA regulation in the pathogenesis of the aforementioned allergic diseases is supported by many studies, but also in other allergic diseases such as food allergy or chronic rhinosinusitis the evidence for a role of miRNAs is emerging. 4,10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Figure 2 provides an overview of miRNAs in cells and tissues that are associated with allergic diseases presented herein.…”

Role of microRNAs in inflammatory upper airway diseases

“…On the other hand, other families were differentially represented, such as miR‐378, miR‐449, and miR‐548. Interestingly, miRNAs belonging to the miR ‐ 449 families are crucial to trigger multi‐ciliogenesis by suppressing cell cycle genes and the Notch pathway in the surface of some vertebrate epithelia 69 . On day 28, we found that the miRNA families similarly represented in CRSwNP and in the control group were miR‐17, miR‐188, miR‐449, miR‐548, and miR‐8.…”

“…We demonstrated for the first time that the genetic transcriptional program responsible for ciliogenesis and cilia function is significantly impaired in CRSwNP epithelium respect to normal epithelium. We suggest that this alteration is due to a different expression profile of miRNAs, particularly of those belonging to mir‐34 and mir‐449 families 69 (Figure 3C).…”

Downregulation of miR‑29b‑3p promotes α‑tubulin deacetylation by targeting the interaction of matrix metalloproteinase‑9 with integrin β1 in nasal polyps

“…Ciliogenesis and cilia function are significantly impaired in the CRSwNPs epithelium, presumably due to the altered expression of miRNAs ( 30 ). The function of miRNAs in CRSwNPs remains unclear.…”

“…For example, miR-29b-3p can directly and indirectly regulate MMP-2 and MMP-9 expression ( 28 , 29 ). A recent study showed that ciliogenesis and cilia function are significantly impaired in the CRSwNPs epithelium, presumably due to the altered expression of miRNAs ( 30 ). Zhang et al ( 31 ) found that overexpression of miR-30a-5p can attenuate the epithelial-mesenchymal transition by repressing CDK6 expression in nasal polyps ( 31 ).…”