Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa

Noriko Umegaki, Anna M G Pasmooij, Munenari Itoh, Jane E. Cerise, Zongyou Guo, Brynn Levy, Antoni Gostyñski, Lisa R. Rothman, Marcel F. Jonkman, Angela M. Christiano

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalScience Translational Medicine
Volume6
Issue number264
DOIs
Publication statusPublished - 2014 Nov 26
Externally publishedYes

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Epidermolysis Bullosa
Induced Pluripotent Stem Cells
Keratinocytes
Therapeutics
Skin
Mutation
Targeted Gene Repair
Junctional Epidermolysis Bullosa
Inborn Genetic Diseases
Mosaicism
Gene Expression Profiling
Genetic Therapy
Genes
Cicatrix
Fibroblasts
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

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Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa. / Umegaki, Noriko; Pasmooij, Anna M G; Itoh, Munenari; Cerise, Jane E.; Guo, Zongyou; Levy, Brynn; Gostyñski, Antoni; Rothman, Lisa R.; Jonkman, Marcel F.; Christiano, Angela M.

In: Science Translational Medicine, Vol. 6, No. 264, 26.11.2014.

Research output: Contribution to journalArticle

Umegaki, N, Pasmooij, AMG, Itoh, M, Cerise, JE, Guo, Z, Levy, B, Gostyñski, A, Rothman, LR, Jonkman, MF & Christiano, AM 2014, 'Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa', Science Translational Medicine, vol. 6, no. 264. https://doi.org/10.1126/scitranslmed.3009342
Umegaki, Noriko ; Pasmooij, Anna M G ; Itoh, Munenari ; Cerise, Jane E. ; Guo, Zongyou ; Levy, Brynn ; Gostyñski, Antoni ; Rothman, Lisa R. ; Jonkman, Marcel F. ; Christiano, Angela M. / Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa. In: Science Translational Medicine. 2014 ; Vol. 6, No. 264.
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