Abstract
Pulmonary failure is the main cause of morbidity and mortality in the human chromosomal instability syndrome Ataxia-telangiectasia (A-T). Major phenotypes include recurrent respiratory tract infections and bronchiectasis, aspiration, respiratory muscle abnormalities, interstitial lung disease, and pulmonary fibrosis. At present, no effective pulmonary therapy for A-T exists. Cell therapy using adipose-derived mesenchymal stromal/stem cells (ASCs) might be a promising approach for tissue regeneration. The aim of the present project was to investigate whether ASCs migrate into the injured lung parenchyma of Atm-deficient mice as an indication of incipient tissue damage during A-T. Therefore, ASCs isolated from luciferase transgenic mice (mASCs) were intravenously transplanted into Atm-deficient and wild-type mice. Retention kinetics of the cells were monitored using in vivo bioluminescence imaging (BLI) and completed by subsequent verification using quantitative real-time polymerase chain reaction (qRT-PCR). The in vivo imaging and the qPCR results demonstrated migration accompanied by a significantly longer retention time of transplanted mASCs in the lung parenchyma of Atm-deficient mice compared to wild type mice. In conclusion, our study suggests incipient damage in the lung parenchyma of Atm-deficient mice. In addition, our data further demonstrate that a combination of luciferase-based PCR together with BLI is a pivotal tool for tracking mASCs after transplantation in models of inflammatory lung diseases such as A-T.
Highlights
Pulmonary failure is a frequent cause of morbidity and mortality in Ataxia-telangiectasia (A-T).At present, no effective pulmonary therapy for A-T exists [1]
−/− ) mice stained with hematoxylin and eosin (A,B) or wild-type (WT)injury and (B,D)
Lung function testing and usingeosin a FlexiVent type (WT) and (B,D) Atm-deficient (Atm ) mice stained with hematoxylin (A,B) ormouse with
Summary
Pulmonary failure is a frequent cause of morbidity and mortality in Ataxia-telangiectasia (A-T).At present, no effective pulmonary therapy for A-T exists [1]. Aside from immunodeficiency and inflammation, fibrotic changes are a major factor leading to progressive lung. We provided evidence for reduced lung function and increased inflammation in the lung of Atm-deficient mice displaying the human pulmonary A-T phenotype [3]. We demonstrated that bone marrow transplantation (BMT) significantly improves the immunological phenotype and inhibits tumorigenesis in Atm-deficient mice [4]. Donor bone marrow derived cells (BMDCs) migrated into bone marrow, blood, thymus, spleen, and lung tissue of Atm-deficient mice. The BMT overcame the immunodeficiency, migration of the donor cells into the lung tissue was low, and most of the cells were of hematopoietic origin. To improve cellular migration and to provide anti-inflammatory, anti-fibrotic, and anti-oxidative activity, a promising approach could be transplantation of mesenchymal stromal/stem cells (MSCs)
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