title: Obesity and Type 2 Diabetes Alters the Immune Properties of Human Adipose Derived Stem Cells.
abstract: Adipose tissue-derived stem cells (ASCs) are proposed as an alternative stem cell source to bone marrow-derived cells for immune cell therapy. However, microenvironmental factors may impact the functionality of this population in human adipose tissue (AT). We hypothesized that the fat depot in addition to the donor phenotype controls the immunomodulatory capacity of ASCs. Focusing on obesity and type 2 diabetes (T2D) as metabolic disorders that might affect the immune response of ASCs, we compared the inflammatory response of ASCs from subcutaneous and visceral AT of age-matched donors (lean n = 4, body mass index [BMI] 21.98 ± 1.9; obese n = 4 BMI 33.1 ± 2.1 and T2D n = 4 BMI 35.3 ± 1.5). Obese and particularly T2D-derived ASCs showed increased expression of inflammatory markers, activation of NLRP3 inflammasome and higher migration, invasion and phagocytosis capacities than those derived from lean donors. Remarkably, ASCs derived from obese and T2D subjects exhibited a reduction in typical immunosuppressive activities attributed to stem cells. Accordingly, obese and T2D-ASCs were less effective in suppressing lymphocyte proliferation, activating the M2 macrophage phenotype, and in increasing TGF-β1 secretion, than lean-derived ASCs. Treatment of lean hASCs with interleukin (IL)-1β mimicked the dysfunctional immune behavior of obese and T2D hASCs. Conversely, combined treatment with IL1RA and TGF-β1 reverted the phenotype of obese- and T2D-ASCs. These data indicate that the donor metabolic phenotype compromises the immunomodulatory properties of ASCs. These results are relevant not only for understanding the physiology of ASCs in terms of cell-based therapies but also for their role as key regulators of the immune response. Stem Cells 2016;34:2559-2573.
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Serena
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Keiran
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ceperuelo-Mallafre
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ejarque
authors.affiliation: Hospital St. Pau I Sta Tecla, Tarragona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Fradera
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Kelly
authors.initials: K
authors.lastname: Roche
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Catalina
authors.initials: C
authors.lastname: Nuñez-Roa
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain. jvo@comt.es.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain. jvo@comt.es.
authors.forename: Joan
authors.initials: J
authors.lastname: Vendrell
authors.affiliation: Hospital Universitari De Tarragona Joan XXIII, Institut D´Investigació Sanitària Pere Virgili, Universitat Rovira I Virgili, Tarragona, Spain. sonia.fernandezveledo@gmail.com.|Instituto De Salud Carlos III, CIBER De Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain. sonia.fernandezveledo@gmail.com.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000473:pathology*; D010587:Phagocytosis; D013234:Stem Cells / Q000276:immunology* / Q000378:metabolism; D014019:Tissue Donors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D053773:Transforming Growth Factor beta1
keywords: Diabetes; Human adipose stem cells; Immunosuppression; Inflammasome; Inflammation; Invasion; Macrophages; Migration; Obesity; Phagocytosis