Mesenchymal stem cells derived biospheres as a potential therapeutic agent in a lung disease immunodeficient murine model of idiopathic pulmonary fibrosis

Abstract

[eng] Idiopathic pulmonary fibrosis (IPF) is a highly mortal, chronic, and irreversible lung disease characterized by inflammation and structural abnormalities of the tissue leading to progressive pulmonary fibrosis. Approximately 3 million people worldwide suffer from this condition and only two pharmacological treatments are approved: pirfenidone and nintedanib. These drugs slow IPF progression but do not cure it. Due to this, mesenchymal stem cells (MSCs) are being explored as therapeutic agents for IPF because they are multipotent cells with potent regenerative and immunomodulatory capacities that could ameliorate fibrosis effects. MSCs in the form of 3D spheroids, which are denominated as “biospheres” (BS), have shown improved in vivo post-grafting survival rates and other advantages in comparison to traditional 2D suspension MSCs. This Master Thesis is based on the hypothesis that mesenchymal stem cells in the form of BS might be an improved therapeutic approach to treat IPF. The objective of this project was to define the basis of an experimental animal model for IPF with bleomycin (BLM) induced lung fibrosis in Swiss Nude Mice Crl:NU(Ico)-Foxn1nu with a treatment with human umbilical cord MSCs (UC-MSCs) in suspension and biosphere presentation. Results showed a clear tendency for MSCs treated groups, in special BS MSCs, to present ameliorated fibrosis effects in response to BLM-induced lung injury. On a cellular level, there was evidence of human mitochondria from the grafted stem cells at an intracellular level in lung epithelium. On a histopathological level, biosphere treated animals showed the lower Ashcroft scores. On a molecular level, BLM+Biospheres treated mice showed higher levels of mitochondrial DNA than MSCs in suspension form. Finally, BLM+BS treated mice showed the lowest concentrations of leukocytes which could be inferred to lower inflammation.