HED-Derived iPSCs Reveal Neurofunctional Defects in Ectodermal Dysplasia

Abstract

Ectodermal dysplasia (ED) is characterized by sparse hair, reduced sweat gland secretion, and congenital absence of teeth. While genes such as EDA and EDAR have been identified as causative factors of ED, the underlying mechanisms remain unknown, and corresponding treatments are not available. Here, we report a pedigree with hypohidrotic ectodermal dysplasia (HED), the most common subtype of ED, caused by a mutation in the KDF1 gene. To investigate disease mechanisms, we generated induced pluripotent stem cells (iPSCs) of family members. Upon differentiation into embryoid bodies (EBs), the KDF1 mutation severely impaired EB size and morphology. The single-cell RNA sequencing further demonstrated that iPSCs from both HED patients showed a specific shortage of several cell populations, whose biological characteristics were closely related to synapse structure and signaling. Initially, iPSCs were differentiated into neurons to analyze their functional changes. Concurrently, patient-derived iPSCs were differentiated into epidermal progenitor cells, and the effect of the N-methyl-D-aspartate receptor antagonist MK-801 during this process was investigated. We found that the overexpression of excitatory neurotransmitters might disrupt ectodermal development. These deficits were partially rescued after CRISPR-mediated correction of the KDF1 mutation. Our work suggests that impaired synaptic structure and signaling impede ectodermal organogenesis in HED.