The anti-inflammatory effect of mesenchymal stromal cells in urate crystal-induced arthritis and its mechanism of action
- Autores: Juan Pablo Medina Giménez
- Directores de la Tesis: Gabriel Herrero-Beaumont Cuenca (dir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
- Idioma: inglés
- Número de páginas: 203
- Títulos paralelos:
- El efecto antiinflamatorio de las células estromales mesenquimales en la artritis inducida por urato y su mecanismo de acción
- Tribunal Calificador de la Tesis: Aránzazu Mediero Muñoz (presid.), Benjamín Fernández Gutiérrez (secret.), Marina I. Garín Ferreira (voc.), Mariano Nicolas Andres Collado (voc.), Sonsoles Martín Santamaría (voc.)
- Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
Mesenchymal stromal cells (MSC) have been considered a promising therapeutic tool for the treatment of many autoimmune and inflammatory diseases. However, its efficacy has not been confirmed in most large-scale clinical trials. Up-to-date, most studies have focused on chronic diseases, in which the adaptive and the innate immune responses are integrated, coexisting a complex network of interactions that makes the mechanisms of action involved in the improvement of these conditions difficult to dissect. Thus, in order investigate whether MSC can act specifically on inflammatory response mechanisms, it is necessary to resort to models of acute, self-limited inflammation, only mediated by innate immunity. In this thesis we studied the effect of human adipose tissue-derived MSC administration in an acute auto-limited gouty arthritis model, which is the paradigm of acute joint disease. The flare-up was induced in rabbit knee joints through monosodium urate (MSU) crystals injection.
In order to assess the evolution of acute synovitis, firstly we validated B-mode and power Doppler musculoskeletal ultrasound imaging in our experimental model. Subsequently, we analyzed the effect of MSC therapy in the acute gouty arthritic rabbits. We observed that a single dose of systemically delivered MSC through the auricular artery significantly decreased inflammation shortly after their administration, while no effects were observed after intra-articular MSC injection. We also tested the effect of the systemic infusion of MSC through the right femoral artery, to investigate whether bypassing MSC vascular distribution through the organism could improve its effects in the right arthritic knee. Our results indicated that MSC exerted the same benefit in both limbs. On the other hand, we also tested whether a unique MSC administration was able to modify the inflammatory response of rabbits that underwent an acute gouty relapse induced by the administration of a second injection of MSU crystals into the knee joints. We did not observe a significant improvement in MSC-treated rabbits after the re-aggression. Finally, our results revealed that intra-femoral infusion of MSC in the acute arthritis model reduced the activity of nuclear factor-κB (NF-κB), and decreased the NLR family pyrin domain containing 3 (NLRP3) inflammasome components synthesis and pro-inflammatory cytokine presence in rabbit synovial membranes. Concurrently, MSC induced the synthesis of anti-inflammatory cytokines and promoted M2 macrophage phenotype polarization in damaged synovium. In vitro studies showed that MSC inhibited the expression of different cytokines and NLRP3 inflammasome components in MSU crystal-stimulated THP-1 macrophages.
Altogether, we have demonstrated that systemic administration of a single dose of human MSC relieves a severe acute arthritis flare in rabbit knees, and we have shed some light on the mechanisms involved. Additionally, our findings suggest that MSC could be considered a novel therapeutic alternative for the treatment of acute gouty flares in patients in whom the use of traditional drugs could cause adverse effects.
