Modeling gap junction beta 2 gene-related deafness with human iPSC.

Area of Science:

• Genetics and Molecular Biology
• Stem Cell Research
• Otolaryngology

Background:

• Over 120 genetic loci are linked to non-syndromic deafness.
• Mutations in the gap junction beta 2 gene (GJB2), encoding connexin 26 (CX26), are the leading cause of hereditary deafness globally.
• Previous research established mouse iPSC-derived CX26 cells for in vitro deafness models, but human cell models were lacking.

Purpose of the Study:

• To generate functional connexin 26 (CX26) gap junction-forming cells from human induced pluripotent stem cells (iPSCs).
• To characterize these human iPSC-derived cells for their resemblance to cochlear supporting cells.
• To create in vitro models of GJB2-related deafness using patient-derived iPSCs.

Main Methods:

• Generation of human iPSC-derived CX26 gap junction-forming cells (iCX26GJCs).
• Characterization of iCX26GJCs for cochlear supporting cell markers and gap junction formation.
• Derivation of iCX26GJCs from iPSCs of patients with common Asian GJB2 mutations.

Main Results:

• Successfully generated human iPSC-derived functional CX26 gap junction-forming cells (iCX26GJCs).
• iCX26GJCs exhibited characteristics of cochlear supporting cells, including gap junction plaque formations and co-expression of key markers.
• Patient-derived iCX26GJCs replicated the pathology associated with GJB2-related deafness.

Conclusions:

• Human iPSCs can be differentiated into functional CX26 gap junction-forming cells resembling cochlear supporting cells.
• These iCX26GJCs provide a robust in vitro model for studying GJB2-related deafness.
• The developed models hold potential for advancing therapy development and drug screening for GJB2 mutations.