Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET.
Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18(+) cells but failed to further differentiate into K14(+) cells (epidermis/limbus) or K3/K12(+) cells (corneal epithelium). APR-246 (PRIMA-1(MET)), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.
Institut National de la Santé et de la Recherche Médicale U898,  University of Nice, 06107 Nice,  France.
Ruby
R
Shalom-Feuerstein
Laura
L
Serror
Edith
E
Aberdam
Franz-Josef
FJ
Müller
Hans
H
van Bokhoven
Klas G
KG
Wiman
Huiqing
H
Zhou
Daniel
D
Aberdam
Isabelle
I
Petit
D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002971:Cleft Lip / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002972:Cleft Palate / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004476:Ectodermal Dysplasia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019573:Epithelium, Corneal / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011812:Quinuclidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D050505:Mutant Proteins; D011812:Quinuclidines; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C533410:eprenetapopt