We sought to determine whether an intact bone marrow is essential to lung repair following bleomycin-induced lung injury in mice, and the mechanisms of any protective effects conferred by bone marrow-derived mesenchymal stem cell (BMDMSC) transfer. We found that myelosupression increased susceptibility to bleomycin injury and that BMDMSC transfer was protective. Protection was associated with the differentiation of engrafted BMDMSC into specific and distinct lung cell phenotypes, with an increase in circulating levels of G-CSF and GM-CSF (known for their ability to promote the mobilization of endogenous stem cells) and with a decrease in inflammatory cytokines. In vitro, cells from injured, but not from normal, mouse lung produced soluble factors that caused BMDMSC to proliferate and migrate toward the injured lung. We conclude that bone marrow stem cells are important in the repair of bleomycin-injured lung and that transfer of mesenchymal stem cells protects against the injury. BMDMSC localize to the injured lung and assume lung cell phenotypes, but protection from injury and fibrosis also involves suppression of inflammation and triggering production of reparative growth factors.
A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis.We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs.IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs.Co-localisation and causal modelling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.
Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions. cardiac function ͉ microRNA T he heart is the first organ to form and to function during vertebrate embryogenesis (1). Perturbations in normal cardiac development and function result in a variety of cardiovascular diseases, the overall leading cause of death in developed countries (2, 3). Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy, in which the heart becomes weakened and affects the ability of the cardiovascular system to meet the metabolic demands of the body. DCM, characterized by cardiac chamber dilation and systolic impairment, has been associated with mutation of specific contractile proteins and components of stress sensor machinery (2, 4). However, the regulatory events required for appropriate coordination of contractile function are still elusive.MicroRNAs (miRNAs) are a class of recently discovered Ϸ22-nt regulatory RNAs that posttranscriptionally regulate gene expression (5). Despite the large number of miRNAs identified thus far, the biological roles of most miRNAs and the molecular mechanisms underlying their function remain largely unknown. Emerging evidence suggests that miRNAs play important roles in a variety of biological processes, including cancer and stem cell biology (6, 7). Recent studies uncovered the involvement of several musclespecific miRNAs, miR-1, -133, and -208 in particular, in the regulation of cardiac and skeletal muscle gene expression and muscle proliferation and differentiation (8-11). Specifically, gene targeting studies demonstrate that miR-1 and -208 are required for proper cardiac development and/or function (9,10).In this study, we took a global approach to study cardiac miRNAs by deleting Dicer, an endonuclease required for the processing of all miRNAs, in the heart. Here we report that loss of Dicer results in a dramatic decrease in the level of mature miRNAs. All Dicer mutant mice die postnatally due to severe DCM and heart failure.Furthermore, we have ...
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