PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis

Luz-Crawford P, Ipseiz N, Espinosa-Carrasco G, Caicedo A, Tejedor G, Toupet K, Loriau J, Scholtysek C, Stoll C, Khoury M, Noel D, Jorgensen C, Krönke G, Djouad F (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 75

Pages Range: 2166-2174

Journal Issue: 12

DOI: 10.1136/annrheumdis-2015-208696

Abstract

To define how peroxisome proliferator-activated receptor (PPAR) ?/? expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPAR?/? interacts with factors such as nuclear factor-kappa B (NF-?B) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPAR?/? on MSC immunosuppressive properties.We either treated human MSCs (hMSCs) with the irreversible PPAR?/? antagonist (GSK3787) or derived MSCs from mice deficient for PPAR?/? (PPAR?/?(-/-) MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays.Modulation of PPAR?/? expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPAR?/?(-/-) MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPAR?/?(+/+) MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPAR?/?(-/-) MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPAR?/?(+/+) MSCs. The enhanced NO2 production by PPAR?/?(-/-) MSCs was due to the increased retention of NF-?B p65 subunit on the ?B elements of the inducible nitric oxide synthase promoter resulting from PPAR?/? silencing.Our study is the first to show that the inhibition or knockdown of PPAR?/? in MSCs primes their immunoregulatory functions. Thus, the regulation of PPAR?/? expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype.

Authors with CRIS profile

Gerhard Krönke Professur für Translationale Immunologie

Involved external institutions

National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) FR France (FR) Universidad San Francisco de Quito EC Ecuador (EC) Universidad de los Andes CL Chile (CL)

How to cite

APA:

Luz-Crawford, P., Ipseiz, N., Espinosa-Carrasco, G., Caicedo, A., Tejedor, G., Toupet, K.,... Djouad, F. (2016). PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis. Annals of the Rheumatic Diseases, 75(12), 2166-2174. https://doi.org/10.1136/annrheumdis-2015-208696

MLA:

Luz-Crawford, P., et al. "PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis." Annals of the Rheumatic Diseases 75.12 (2016): 2166-2174.

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