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News Round Up: May 12, 2014

Multiple news outlets, including the BBC, Huffington Post, Press TV, and Ani News report on “Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility” by Robyn Klein and colleagues.

Digital Journal covers “Epigenetic reprogramming induces the expansion of cord blood stem cells” by Pratima Chaurasia and colleagues. Read the accompanying Commentary “Inhibiting HDAC for human hematopoietic stem cell expansion’”by Hal Broxmeyer.

Published May 8, 2014, by Corinne Williams

In the News

Related articles

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility
Lillian Cruz-Orengo, … , Seth D. Crosby, Robyn S. Klein
Lillian Cruz-Orengo, … , Seth D. Crosby, Robyn S. Klein
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2571-2584. https://doi.org/10.1172/JCI73408.
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Research Article Autoimmunity

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

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Abstract

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.

Authors

Lillian Cruz-Orengo, Brian P. Daniels, Denise Dorsey, Sarah Alison Basak, José G. Grajales-Reyes, Erin E. McCandless, Laura Piccio, Robert E. Schmidt, Anne H. Cross, Seth D. Crosby, Robyn S. Klein

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Epigenetic reprogramming induces the expansion of cord blood stem cells
Pratima Chaurasia, … , Sunita D’Souza, Ronald Hoffman
Pratima Chaurasia, … , Sunita D’Souza, Ronald Hoffman
Published April 24, 2014
Citation Information: J Clin Invest. 2014;124(6):2378-2395. https://doi.org/10.1172/JCI70313.
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Technical Advance

Epigenetic reprogramming induces the expansion of cord blood stem cells

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Abstract

Cord blood (CB) cells that express CD34 have extensive hematopoietic capacity and rapidly divide ex vivo in the presence of cytokine combinations; however, many of these CB CD34+ cells lose their marrow-repopulating potential. To overcome this decline in function, we treated dividing CB CD34+ cells ex vivo with several histone deacetylase inhibitors (HDACIs). Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune–deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.

Authors

Pratima Chaurasia, David C. Gajzer, Christoph Schaniel, Sunita D’Souza, Ronald Hoffman

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Inhibiting HDAC for human hematopoietic stem cell expansion
Hal E. Broxmeyer
Hal E. Broxmeyer
Published April 24, 2014
Citation Information: J Clin Invest. 2014;124(6):2365-2368. https://doi.org/10.1172/JCI75803.
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Commentary

Inhibiting HDAC for human hematopoietic stem cell expansion

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Abstract

In this issue of the JCI, Chaurasia and colleagues report an impressive ex vivo expansion of HSCs from human cord blood (CB) using cytokines and altering epigenetic modifications. The application of this protocol provides information that has potential for clinical consideration. The enhanced expansion of CB HSCs is a substantial advance over recent work from the Chaurasia and Hoffman group, in which ex vivo production of human erythroid progenitor cells from CB was promoted by chromatin modification. Moreover, this study takes advantage of information from the rapidly emerging, but not yet fully elucidated, field of epigenetics.

Authors

Hal E. Broxmeyer

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