Mesenchymal stromal cells in lung tissue

Sammanfattning: Mesenchymal stromal cells (MSC) are multipotent cells with immunomodulatory and regenerative properties. During recent years, the interest in using MSC for clinical approaches for various diseases have increased. The lung field is no exception, and several clinical trials using MSC as a cell-based therapy for severe lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and severe emphysema have been performed. Another severe lung disease where MSC therapy might be an alternative is bronchiolitis obliterans syndrome (BOS), a chronic type of rejection affecting approxamately 50% of lung transplanted patients within five years after transplantation. The exact pathology of BOS is at present not known, but inflammation is thought to be an important driving factor. Despite an increased interest in using MSC as a therapy, the in vivo biological function of endogenous MSC is not completely known. Furthermore, the cellular identity of primary MSC in human lungs has not been reported. The aim of this thesis work has been to provide new insights of MSC in lung tissue, especially after lung transplantation, with respect to origin, tissue-specificity, and extracellular matrix production. Primary and culture-derived MSC were isolated from lung biopsies obtained from lung transplanted patients, fetal lung tissue, and bone marrow aspirates and evaluated using a comprehensive panel of in vitro and in vivo assays. The studies show that lung-derived MSC are tissue-resident cells with tissue-specific properties. Lung-derived MSC have different gene expression- and cytokine patterns, higher proliferation rate, higher colony-forming capacity, and smaller size compared with bone marrow-derived MSC. Interestigly, lung-derived MSC do not have in vivo bone formation capacity. Furthermore, we demonstrate for the first time that primary lung-derived MSC are enriched in the CD90+/CD105+ mononuclear cell fraction, which have a perivascular location in situ. Additionally, we demonstrate that MSC are prominent extracellular matrix producers, and that bone marrow- and lung-derived MSC produce distinct extracellular matrix profiles. There were no significant differenses between patients with chronic and acute rejections compared with good outcome recipients regarding EDA-fibronectin expression. However, increased EDA-fibronectin expression was found in acute rejections grade A2-A3 and in biopsies from patients with infection. Finally, these studies show that tissue-resident MSC do not have an altered phenotype after BOS development and that the number of colony-forming cells i.e. MSC do not correlate with the onset of BOS. In summary, this thesis work provide novel insights of tissue-resident MSC within the lung, an important step in identifying the functional role of MSC in normal lung physiology and during disease. Hopefully in the future, this knowledge will improve clinical strategies to treat severe lung diseases such as BOS.