Characterisation of bone marrow progenitor cells in disease

Abstract

The bone marrow serves as a reservoir for leukocytes and stem cells, from where cells can be mobilised into the circulation and can be recruited to sites of inflammation. Mobilisation of cells out of the bone marrow is dependent on their migration across the bone marrow sinusoidal endothelium, which is thought to be structurally and functionally different to endothelial cells from other vascular beds. In order to characterise the bone marrow endothelium and to study the molecular mechanisms involved in the mobilisation of cells, a protocol to isolate bone marrow endothelial cells and to grow them in vitro was developed. The bone marrow contains a number of distinct progenitor cell populations, including endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs). Whether these populations of stem cells are recruited from the bone marrow to the lungs was investigated in two contrasting models of lung disease: the house dust mite (HDM) model of allergic airways disease and the bleomycin model of pulmonary fibrosis. In the HDM model increased recruitment of EPCs to the inflamed lungs was associated with increased peribronchial angiogenesis, and reduced EPC numbers in the bone marrow. Blocking VEGF inhibited EPC recruitment to the inflamed lungs and reduced the associated peribronchial angiogenesis. In this model, no recruitment of MSCs to the inflamed lungs was observed. However, in the bleomycin model, a significant elevation in MSC numbers was observed in the circulation, lung tissue and BAL fluid. Experiments to block the recruitment of MSCs to the lungs in response to bleomycin injury were performed, along with investigations into the recruitment of exogenously administered MSCs to the injured lungs. A population of MSCs residing in the naïve lungs was identified, which are phenotypically similar to bone marrow MSCs, but can be distinguished by their size and expression of specific cell surface antigens.