title: Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa.
abstract: Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic gene mutation in a somatic cell. It has been observed in several genetic diseases, including epidermolysis bullosa (EB), a group of inherited skin disorders characterized by blistering and scarring. Induced pluripotent stem cells (iPSCs), generated from fibroblasts or keratinocytes, have been proposed as a treatment for EB. However, this requires genome editing to correct the mutations, and, in gene therapy, efficiency of targeted gene correction and deleterious genomic modifications are still limitations of translation. We demonstrate the generation of iPSCs from revertant keratinocytes of a junctional EB patient with compound heterozygous COL17A1 mutations. These revertant iPSCs were then differentiated into naturally genetically corrected keratinocytes that expressed type XVII collagen (Col17). Gene expression profiling showed a strong correlation between gene expression in revertant iPSC-derived keratinocytes and the original revertant keratinocytes, indicating the successful differentiation of iPSCs into the keratinocyte lineage. Revertant-iPSC keratinocytes were then used to create in vitro three-dimensional skin equivalents and reconstitute human skin in vivo in mice, both of which expressed Col17 in the basal layer. Therefore, revertant keratinocytes may be a viable source of spontaneously gene-corrected cells for developing iPSC-based therapeutic approaches in EB.
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Umegaki-Arao
authors.affiliation: Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
authors.forename: Anna M G
authors.initials: AM
authors.lastname: Pasmooij
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA. Department of Dermatology, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Munenari
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Cerise
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Zongyou
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Brynn
authors.initials: B
authors.lastname: Levy
authors.affiliation: Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
authors.forename: Antoni
authors.initials: A
authors.lastname: Gostyński
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Rothman
authors.affiliation: Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA. Department of Genetics and Development, Columbia University, New York, NY 10032, USA. amc65@columbia.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D004820:Epidermolysis Bullosa / Q000473:pathology / Q000628:therapy*; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009030:Mosaicism; D024041:Non-Fibrillar Collagens / Q000235:genetics; D012867:Skin / Q000473:pathology; D014158:Transcription, Genetic; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII