Multiomics Analysis of a DNAH5-Mutated PCD Organoid Model Revealed the Key Role of the TGF-β/BMP and Notch Pathways in Epithelial Differentiation and the Immune Response in DNAH5-Mutated Patients

Cells. 2022 Dec 12;11(24):4013. doi: 10.3390/cells11244013.

Abstract

Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a child PCD airway organoid directly from the bronchoscopic biopsy of a patient with the DNAH5 mutation. The motile cilia in the organoid were observed and could be stably maintained for an extended time. We further found abnormal ciliary function and a decreased immune response caused by the DNAH5 mutation through single-cell RNA sequencing (scRNA-Seq) and proteomic analyses. Additionally, the directed induction of the ciliated cells, regulated by TGF-β/BMP and the Notch pathway, also increased the expression of inflammatory cytokines. Taken together, these results demonstrated that the combination of multiomics analysis and organoid modelling could reveal the close connection between the immune response and the DNAH5 gene.

Keywords: DNAH5; airway organoid; immune response; multiomics analysis; primary ciliary dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axonemal Dyneins* / genetics
  • Cell Differentiation / genetics
  • Child
  • Humans
  • Kartagener Syndrome* / genetics
  • Multiomics
  • Organoids
  • Proteomics
  • Transforming Growth Factor beta

Substances

  • Axonemal Dyneins
  • Transforming Growth Factor beta
  • DNAH5 protein, human

Grants and funding

This study was partially supported by grant 22ZDZX0014 from the Science and Technology Department of Sichuan Province, the clinical development grant from West China Second University Hospital of Sichuan University (KL118), the Fundamental Research Funds for the Central Universities (SCU2022D022), the National Natural Science Foundation of China Joint Fund for Regional Innovation and Development (U21A20333) and the Central Government Funds of Guiding Local Scientific and Technological Development for Sichuan Province (No. 2021ZYD0105). The APC was funded by the clinical development grant of West China Second University Hospital of Sichuan University (KL118). We thank all the members in the Hanmin Liu laboratory for their helpful discussions and support.