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Prominin-1/CD133⁺ Lung Epithelial Progenitors Protect from Bleomycin-induced Pulmonary Fibrosis

¹ Experimental Critical Care Medicine, Department of Biomedicine, University of Basel, Basel, Switzerland; ² Cardiovascular Research, Zurich Center for Integrative Human Physiology, University Zurich-Irchel, Zurich, Switzerland; ³ Department of Pathology, University Hospital, Basel, Switzerland; ⁴ Department of Cardiology, University Hospital, Zurich, Switzerland; ⁵ Department of Internal Medicine and ⁶ Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Basel, Switzerland

Correspondence and requests for reprints should be addressed to Davide Germano, Ph.D., Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland. E-mail: davide.germano{at}unibas.ch

Rationale: The mouse model of bleomycin-induced lung injury offers an approach to study idiopathic pulmonary fibrosis, a progressive interstitial lung disease with poor prognosis. Progenitor cell–based treatment strategies might combine antiinflammatory effects and the capacity for tissue repair.

Objectives: To expand progenitor cells with reparative and regenerative capacities and to evaluate their protective effects on pulmonary fibrosis in vivo.

Methods: Prominin-1/CD133⁺ epithelial progenitor cells (PEPs) were expanded from adult mouse lungs after digestion and culture of distal airways. Lung fibrosis was induced in C57Bl/6 mice by instillation of bleomycin. Two hours later, animals were transplanted with PEPs. Inflammation and fibrosis were assessed by immunohistochemistry, bronchoalveolar lavage fluid differentials, and real-time polymerase chain reaction.

Measurements and Main Results: PEPs expanded from mouse lungs were of bone marrow origin, coexpressed stem and hematopoietic cell markers, and differentiated in vitro into alveolar type II surfactant protein-C⁺ epithelial cells. In bleomycin-challenged mice, intratracheally injected PEPs engrafted into the lungs and differentiated into type II pneumocytes. Furthermore, PEPs suppressed proinflammatory and profibrotic gene expression, prevented the recruitment of inflammatory cells, and protected bleomycin-challenged mice from pulmonary fibrosis. Mechanistically, the protective effect depended on upregulation of inducible nitric oxide synthase in PEPs and nitric oxide–mediated suppression of alveolar macrophage proliferation. Accordingly, PEPs from iNOS^–/– but not iNOS^+/+ mice failed to protect from bleomycin-induced lung injury.

Conclusions: The combined antiinflammatory and regenerative capacity of bone marrow–derived pulmonary epithelial progenitors offers a promising approach for development of cell-based therapeutic strategies against pulmonary fibrosis.

Key Words: cell therapy • prominin-1 • lung fibrosis • stem cells • inducible nitric oxide synthase

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Lung injury activates tissue resident cells with regenerative capacity. Such cells might become of interest for designing novel cell-based therapies. What This Study Adds to the Field Prominin-1+ epithelial progenitors (PEPs) with antiinflammatory and regenerative capacity can be expanded from healthy mouse lungs. PEPs protect mice in a nitric oxide–dependent manner from bleomycin-induced pulmonary fibrosis.