Identification of a novel population of bone marrow-derived prominin-1/CD133⁺ lung progenitors with regenerative capacity

Germano, Davide. Identification of a novel population of bone marrow-derived prominin-1/CD133⁺ lung progenitors with regenerative capacity. 2008, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8612

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Inflammation-induced lung fibrosis represents a common final pathway of various pulmonary disorders, such as the adult respiratory distress syndrome, or interstitial lung diseases, such as idiopathic pulmonary fibrosis. Endogenous stem/progenitor cells might represent a novel cell-based therapeutic option combining tissue repair and anti-inflammatory effects. Here, we describe the identification of a novel population of prominin1/CD133+ progenitor cells from adult mouse lungs. Following digestion and culture of distal airways, we were able to expand high numbers of prominin-1+ progenitor cells. Prominin-1+ progenitors co-expressed stem and hematopietic cell markers, and were of bone marrow origin as suggested by the analysis of CD45.2 chimeric mice reconstituted with CD45.1 or GFP donor bone marrow. Immunohistochemistry revealed that bone marrow-derived prominin-1+ cells resided in the alveolar epithelium. Prominin-1+ progenitors showed multilineage differentiation capacities in vitro. Depending on culture conditions, they differentiated into alveolar type II surfactant protein-C positive epithelial cells, phagocyting macrophages, or fibroblastlike cells. After intratracheal administration into mice, prominin-1+ progenitor cells engrafted in the alveolar epithelium and differentiated into type II pneumocytes. In order to evaluate the regenerative and anti-inflammatory capacity of prominin-1+ progenitors, we used a mouse model of bleomycin (BLM)-induced lung injury. In this injury model, single intratracheal instillations of BLM into C57Bl/6 mice result in recruitment of inflammatory cells, infiltration of fibroblasts, and excessive collagen deposition and pulmonary fibrosis. In contrast to sham-treated control mice, following intratracheal transplantation of prominin-1+ cells completely protected the animals from fibrosis development. The extent of pulmonary inflammation and fibrosis was assessed by histology, immunohistochemistry, bronchoalveolar lavage fluid differentials, and real-time RT-PCR. Prominin-1+ cells suppressed pro-inflammatory and pro-fibrotic gene expression and prevented the recruitment of inflammatory cells and fibrocytes. Mechanistically, the protective effect depended on the up-regulation of inducible nitric oxide synthase (iNOS) in prominin-1+ progenitor cells and nitric oxide mediated suppression of alveolar macrophage proliferations. Accordingly, prominin-1+ cells expanded from iNOS-/-, but not iNOS+/+ mice, failed to protect from BLM-induced lung injury. In conclusion, the combined immunomodulatory and regenerative capacity of bone marrow-derived prominin-1+ pulmonary progenitors makes them a promising option for novel cell-based treatment strategies against pulmonary fibrosis.
Advisors:Eriksson, Urs
Committee Members:Eberle, Alex N. and Arber, Silvia
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Experimental Critical Care Medicine (Eriksson)
UniBasel Contributors:Eriksson, Urs and Eberle, Alex N. and Arber, Silvia
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8612
Thesis status:Complete
Number of Pages:104
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:51
Deposited On:23 Jul 2009 13:34

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