title: Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs.
  
  
  METHODS
  We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates.
  
  
  RESULTS
  Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4(+)IL17(+), CD11b(+)Ly6G(+) and CD11b(+)Ly6C(+) cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype.
  
  
  CONCLUSIONS
  DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Gene Regulation, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bravo
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Mammary Gland Pathology, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Marta I
authors.initials: MI
authors.lastname: Gallego
authors.affiliation: Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Avda. Córdoba s/n, 28041, Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Flores
authors.affiliation: Hospital Central de Cruz Roja, Servicio de Hematología y Hemoterapia, Avenida de Reina Victoria 24, 28003, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bornstein
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Gene Regulation, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Puente-Bedia
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Gene Regulation, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández
authors.affiliation: Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Avda. Córdoba s/n, 28041, Madrid, Spain.
authors.forename: Paz
authors.initials: P
authors.lastname: de la Torre
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Mammary Gland Pathology, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Zaragoza
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Histology Core Unit, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez-Tavarez
authors.affiliation: Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Avda. Córdoba s/n, 28041, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Grande
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Gene Regulation, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ballester
authors.affiliation: Instituto de Salud Carlos III, Unidad Funcional de Investigación en Enfermedades Crónicas, Laboratory of Gene Regulation, Carretera de Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain. sballes@isciii.es.
authors.forename: Sara
authors.initials: S
authors.lastname: Ballester
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D022423:Myeloid Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
keywords: EAE; Immunomodulation; Placental mesenchymal stem cells; Th17