Rapid generation of Col7a1-/- mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells

Authors

Beau R. Webber
Kyle T. O'Connor
Ron T. MElmurry
Elise N. Durgin
Cindy R. Eide
Christopher J. Lees
Megan J. Riddle
Wendy E. Mathews
Natasha Y. Frank
Mark A. Kluth
Christoph Ganss
Branden S. Moriarity
Markus H. Frank, Edith Cowan UniversityFollow
Mark J. Osborn
Jakup Tolar

Document Type

Journal Article

Publication Title

Laboratory Investigation

Publisher

Nature Publishing Group

Place of Publication

United States

School

School of Medical and Health Sciences

RAS ID

26406

Comments

Webber, B. R., O'Connor, K. T., McElmurry, R. T., Durgin, E. N., Eide, C. R., Lees, C. J., . . . Ganss, C. (2017). Rapid generation of Col7a1 (-/-) mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells. Laboratory investigation, 97(10), 1218-1224. https://doi.org/10.1038/labinvest.2017.85

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating and ultimately lethal blistering disease caused by mutations to the Col7a1 gene. Development of novel cell therapies for the treatment of RDEB would be fostered by having immunodeficient mouse models able to accept human cell grafts; however, immunodeficient models of many genodermatoses such as RDEB are lacking. To overcome this limitation, we combined the clustered regularly interspaced short palindromic repeats and associated nuclease (CRISPR/Cas9) system with microinjection into NOD/SCID IL2rγcnull (NSG) embryos to rapidly develop an immunodeficient Col7a1-/- mouse model of RDEB. Through dose optimization, we achieve F0 biallelic knockout efficiencies exceeding 80%, allowing us to quickly generate large numbers of RDEB NSG mice for experimental use. Using this strategy, we clearly demonstrate important strain-specific differences in RDEB pathology that could underlie discordant results observed between independent studies and establish the utility of this system in proof-of-concept human cellular transplantation experiments. Importantly, we uncover the ability of a recently identified skin resident immunomodulatory dermal mesenchymal stem cell marked by ABCB5 to reduce RDEB pathology and markedly extend the lifespan of RDEB NSG mice via reduced skin infiltration of inflammatory myeloid derivatives.

DOI

10.1038/labinvest.2017.85

Access Rights

free_to_read