Paper dels productes derivats de les cèl·lules mare mesenquimals en asma experimental
- Autores: Rubén Osuna Gómez
- Directores de la Tesis: David Ramos Barbón (dir. tes.), Eder Fredy Mateus Medina (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
- Idioma: español
- ISBN: 9788449096518
- Tribunal Calificador de la Tesis: César Picado Vallés (presid.), Carlos Zamora Atenza (secret.), M. Jesús Cruz Carmona (voc.)
- Programa de doctorado: Programa de Doctorado en Inmunología Avanzada por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Asthma is a chronic inflammatory disease that affects approximately 300 million people worldwide. During the last decades, its prevalence, morbidity, and mortality have increased especially in industrialized countries. This disease is mainly characterized by a set of structural alterations in the respiratory tract, defined by the term "remodeling", which has been associated with the severity of the disease. Among these alterations, the increase in smooth muscle mass induced by hyperplasia and hypertrophy of smooth muscle cells are crucial factors due to their influence on irreversible airflow obstruction and airway hyperreactivity. Currently, asthma treatments based on the control of inflammation have not demonstrated relevant effects on the remodeling mechanism. The only treatment with the capacity to act on this alteration is invasive thermoplasty, with controversial cost-effectiveness and therapeutic failures. In this context, mesenchymal stem cells (MSC) have a potential therapeutic interest in bronchial remodeling due to their immunoregulatory effects. However, their infusion as a chronic therapy may induce recruitment and differentiation of these cells, which may then participate in airway remodeling, particularly in the smooth muscle growth. However, data from experimental asthma models suggest an anti-remodeling therapeutic effect of MSC, carried by soluble mediators. There is, therefore, a need to understand the immunological mechanisms that contribute to the remodeling process and develop experimental animal models capable of reproducing the physiopathological mechanisms as closely as possible to humans, to provide a better understanding and treatment of asthma. In the present doctoral thesis, it was proposed to develop an allergic asthma model based on primary airway exposure to allergen, to study the implication of MSC in airway remodeling in vitro. Additionally, the immunomodulatory mechanisms of the MSC were studied as a suppressive therapy on airway smooth muscle remodeling by in vitro co-culture systems, and in the in vivo model developed. The results obtained demonstrate a significant role of allergen-specific CD4+ T cells in smooth muscle proliferation through direct cell contact, which was measured by cell cycle analysis through flow cytometry. Additionally, MSC are able to inhibit smooth muscle cell proliferation induced by CD4+ T cells only when they were separated by "Transwell" permeable membranes, and were at high MSC: lymphocyte ratios. Moreover, it was observed that such suppressive effect was not carried by exosomes but mediated by secreted, soluble molecules without prior signaling. Only soluble factors in a range of 30 to 100 kDa molecular weight of MSC-conditioned medium (CM) are capable of suppress smooth muscle cell proliferation. This 30-100-kDa CM, when tested at different doses in vivo in the asthma model, demonstrated a suppressive effect on inflammation and airway remodeling, provided that the animals were treated with repeated low-dose CM. This effect was possibly generated by a deviation of the Th2 immune response towards a Th1/Th17 phenotype in the respiratory tract. In this context, the MSC CM is postulated as a promising therapeutic strategy to reverse airway remodeling through a deviation of the immune response.
