Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Cell Adhesion
Cell Adhesion Molecules
/ biosynthesis
Cell Cycle Proteins
/ genetics
Cell Line
Epidermis
/ metabolism
Epidermolysis Bullosa
/ genetics
Genetic Therapy
Humans
Keratinocytes
/ metabolism
Mice
Stem Cells
/ metabolism
Transcription Factors
/ genetics
YAP-Signaling Proteins
Kalinin
YAP
cell and gene therapy
epidermal stem cells
epidermolysis bullosa
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
14 05 2019
14 05 2019
Historique:
received:
30
11
2018
revised:
12
03
2019
accepted:
10
04
2019
entrez:
16
5
2019
pubmed:
16
5
2019
medline:
2
7
2020
Statut:
ppublish
Résumé
Laminin 332-deficient junctional epidermolysis bullosa (JEB) is a severe genetic skin disease. JEB is marked by epidermal stem cell depletion, the origin of which is unknown. We show that dysregulation of the YAP and TAZ pathway underpins such stem cell depletion. Laminin 332-mediated YAP activity sustains human epidermal stem cells, detected as holoclones. Ablation of YAP selectively depletes holoclones, while enforced YAP blocks conversion of stem cells into progenitors and indefinitely extends the keratinocyte lifespan. YAP is dramatically decreased in JEB keratinocytes, which contain only phosphorylated, inactive YAP. In normal keratinocytes, laminin 332 and α6β4 ablation abolish YAP activity and recapitulate the JEB phenotype. In JEB keratinocytes, laminin 332-gene therapy rescues YAP activity and epidermal stem cells in vitro and in vivo. In JEB cells, enforced YAP recapitulates laminin 332-gene therapy, thus uncoupling adhesion from proliferation in epidermal stem cells. This work has important clinical implication for ex vivo gene therapy of JEB.
Identifiants
pubmed: 31091444
pii: S2211-1247(19)30528-5
doi: 10.1016/j.celrep.2019.04.055
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Adhesion Molecules
0
Cell Cycle Proteins
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Yap1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2036-2049.e6Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.