Browsing by Author "Vega-Letter, Ana María"
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Item IL17/IL17RA as a Novel Signaling Axis Driving Mesenchymal Stem Cell Therapeutic Function in Experimental Autoimmune Encephalomyelitis(2018) Kurte, Mónica; Luz-Crawford, Patricia; Vega-Letter, Ana María; Contreras, Rafael A.; Tejedor, Gautier; Elizondo-Vega, Roberto; Martinez-Viola, Luna; Fernández- O’Ryan, Catalina; Figueroa, Fernando E.; Jorgensen, Christian; Djouad, Farida; Carrión, FlavioThe therapeutic effect of mesenchymal stem cells (MSCs) in multiple sclerosis (MS) and the experimental autoimmune encephalomyelitis (EAE) model has been well described. This effect is, in part, mediated through the inhibition of IL17-producing cells and the generation of regulatory T cells. While proinflammatory cytokines such as IFNγ, TNFα, and IL1β have been shown to enhance MSCs immunosuppressive function, the role of IL17 remains poorly elucidated. The aim of this study was, therefore, to investigate the role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing on Th17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro, we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation and differentiation is partially dependent on IL17RA expression. This was associated with a reduced expression level of MSCs immunosuppressive mediators such as VCAM1, ICAM1, and PD-L1 in IL17RA−/− MSCs as compared to wild-type (WT) MSCs. In the EAE model, we demonstrated that while WT MSCs significantly reduced the clinical scores of the disease, IL17RA−/− MSCs injected mice exhibited a clinical worsening of the disease. The disability of IL17RA−/− MSCs to reduce the progression of the disease paralleled the inability of these cells to reduce the frequency of Th17 cells in the draining lymph node of the mice as compared to WT MSCs. Moreover, we showed that the therapeutic effect of MSCs was correlated with the generation of classical Treg bearing the CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveal a novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAE and suggest that the modulation of IL17RA in MSCs could represent a novel method to enhance their therapeutic effect in MS.Item Mesenchymal Stem Cells Derived from Human Inflamed Dental Pulp Exhibit Impaired Immunomodulatory Capacity In Vitro(2020) Inostroza, Carolina; Vega-Letter, Ana María; Brizuela, Claudia; Castrillón, Luis; Saint Jean, Nicole; Mira Duran, Carol; Carrión, FlavioIntroduction:Dental pulp stem cells (DPSC) are very attractive in regenerative medicine. Inthis study, we focused on the characterization of the functional properties of mesenchymalstem cells derived from DPSCs. Currently, it is unknown whether inflammatory conditionspresent in an inflamed dental pulp tissue could alter the immunomodulatory properties ofDPSCs. This study aimed to evaluate the immunomodulatory capacityin vitroof DPSCsderived from healthy and inflamed dental pulp.Methods:DPSCs from 10 healthy andinflamed dental pulps (irreversible pulpitis) were characterized according to the minimal criteriaof the International Society for Cell Therapy, proliferation, differential potential, and colony-forming units. Furthermore, the immunomodulatory capacity of DPSCs was tested on theproliferation of T lymphocytes byflow cytometry and thein vitroenzyme activity of indoleamine2, 3-dioxygenase. Results:There were no significant differences in the DPSC characteristicsand properties such as immunophenotype, tridifferentiation, colony-forming units, and pro-liferation of the DPSCs derived from normal and inflamed pulp tissue. Furthermore, there weresignificant differences in the immunomodulatory capacity of DPSCs obtained from humanhealthy dental pulp and with the diagnosis of irreversible pulpitis. Conclusions:Our resultsshowed that DPSCs isolated from inflamed dental pulp showed typical characteristics ofMSCs and diminished immunosuppressive capacityin vitroin comparison with MSCs derivedfrom healthy dental pulp. Further investigationin vivois needed to clarify the mechanism of thisdiminished immunosuppressive capacity.Item Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE(2020) Kurte, Mónica; Vega-Letter, Ana María; Luz-Crawford, Patricia; Djouad, Farida; Noël, Danièle; Khoury, Maroun; Carrión, FlavioBackground: Mesenchymal stem cells (MSCs) have been recognized for their regenerative and anti-inflammatory capacity which makes them very attractive to cell therapy, especially those ones to treat inflammatory and autoimmune disease. Two different immune-phenotypes have been described for MSCs depending on which Tolllike receptor (TLR) is activated. MSC1 is endowed with a pro-inflammatory phenotype following TLR4 activation with LPS. On the other hand, anti-inflammatory MSC2 is induced by the activation of TLR3 with Poly(I:C). High immunoplasticity of MSCs is a matter of concern in cell-based therapies. In this study, we investigated whether a single stimulus can induce both types of MSCs through a differential activation of TLR4 with LPS. Methods: MSCs were activated with LPS following a short exposure of 1-h (MSCs-LPS1h) or long-time exposure for 48 h (MSCs-LPS48h), and then, we evaluated the biological response in vitro, the immunosuppressive capacity of MSCs in vitro, and the therapeutic potential of MSCs in an experimental autoimmune encephalomyelitis (EAE) mouse model. Results: Our results showed that 1-h LPS exposure induced a MSC1 phenotype. Indeed, MSCs-LPS1h expressed low levels of NO/iNOS and decreased immunosuppressive capacity in vitro without therapeutic effect in the EAE model. In contrast, MSCs-LPS48h achieved a MSC2-like phenotype with significant increase in the immunosuppressive capacity on T cell proliferation in vitro, together with an improved in the therapeutic effect and higher Treg, compared to unstimulated MSCs. Furthermore, we determine through the MSCs-TLR4KO that the expression of TLR4 receptor is essential for MSCs’ suppressive activity since TLR4 deletion was associated with a diminished suppressive effect in vitro and a loss of therapeutic effect in vivo. Conclusions: We demonstrate that MSCs display a high immunoplasticity commanded by a single stimulus, where LPS exposure time regulated the MSC suppressive effect leading into either an enhanced or an impairment therapeutic activity. Our results underscore the importance of phenotype conversion probably related to the TLR4 expression and activation, in the design of future clinical protocols to treat patients with inflammatory and autoimmune diseases.