Human Embryonic Stem Cell-Derived Mesenchymal Stromal Cells Decrease the Development of Severe Experimental Autoimmune Uveitis in B10.RIII Mice

<p><i>Purpose</i>: We investigated the effect of exogenously administered human embryonic stem cell-derived mesenchymal stromal cells (hESC-MSCs) in experimental autoimmune uveitis (EAU) in B10.RIII mice, a murine model of severe uveitis.</p> <p><i>Methods</i>: B10.RIII mice were immunized with an uveitogenic peptide, and intraperitoneal injections of 5 million hESC-MSCs per animal were given on the same day. Behavioral light sensitivity assays, histological evaluation, cytokine production, and regulatory T cells were analyzed at the peak of the disease.</p> <p><i>Results</i>: Histological and behavioral evidence demonstrated that early systemic treatment with hESC-MSCs decreases the development of severe EAU in B10.RIII mice. hESC-MSCs suppress Th17 and upregulate Th1 and Th2 responses as well as IL-2 and GM-CSF in splenocytes from hESC-MSC-treated mice.</p> <p><i>Conclusions</i>: MSCs that originate from hESC decrease the development of severe EAU in B10.RIII mice, likely through systemic immune modulation. Further investigation is needed to determine any potential effect on active EAU.</p

<i>In silico</i> prediction tests.

<p>Results for the p.Tyr90Cys variant in <i>ARL3</i>.</p

Evolutionary conservation of exon 5 of ARL3.

<p>Includes the tyrosine (Y) amino acid at position 90 (boxed), across vertebrate species. Representative set of 9 species shown using the UCSC Genome Browser.</p

Variants meeting various filter criteria.

<p>Maximum of 1000 Genomes and Exome Sequencing Project (ESP5400) used as minor allele frequency (MAF). “Problematic gene” is a gene which is known to be poorly assessed by exome sequencing, such as genes in the mucin family and HLA genes.</p

Protein-protein interaction predictions.

<p>Results for the p.Tyr90Cys variant in <i>ARL3</i>. Calculated using the web tool mCSM [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150944#pone.0150944.ref027" target="_blank">27</a>].</p

Pedigree of family with apparent autosomal dominant retinitis pigmentosa.

<p><i>De novo</i> occurrence of a variant in <i>ARL3</i> in an individual with retinitis pigmentosa and subsequent transmission to affected offspring.</p