hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers

Dulce Lima Cunha, Amanda Oram, Robert Gruber, Roswitha Plank, Arno Lingenhel, Manoj K Gupta, Janine Altmüller, Peter Nürnberg, Matthias Schmuth, Johannes Zschocke, Tomo Saric, KATJA ECKL, Hans C Hennies*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

nherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients.
Original languageEnglish
Pages (from-to)1-16
JournalInternational Journal of Molecular Sciences
Volume22
Issue number1785
Early online date11 Feb 2021
DOIs
Publication statusE-pub ahead of print - 11 Feb 2021

Keywords

  • ichthyosis
  • stem cells
  • iPSC
  • keratinocytes
  • Keratinization disorder
  • 3D skin modelling
  • reprogramming
  • lentivirus
  • ARCI
  • mimic phenotype
  • replacing animals

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