Abstract
BackgroundPulmonary fibrosis may result from abnormal alveolar wound repair after injury. Hepatocyte growth factor (HGF) improves alveolar epithelial wound repair in the lung. Stem cells were shown to play a major role in lung injury, repair and fibrosis. We studied the presence, origin and antifibrotic properties of HGF-expressing stem cells in usual interstitial pneumonia.MethodsImmunohistochemistry was performed in lung tissue sections and primary alveolar epithelial cells obtained from patients with usual interstitial pneumonia (UIP, n = 7). Bone marrow derived stromal cells (BMSC) from adult male rats were transfected with HGF, instilled intratracheally into bleomycin injured rat lungs and analyzed 7 and 14 days later.ResultsIn UIP, HGF was expressed in specific cells mainly located in fibrotic areas close to the hyperplastic alveolar epithelium. HGF-positive cells showed strong co-staining for the mesenchymal stem cell markers CD44, CD29, CD105 and CD90, indicating stem cell origin. HGF-positive cells also co-stained for CXCR4 (HGF+/CXCR4+) indicating that they originate from the bone marrow. The stem cell characteristics were confirmed in HGF secreting cells isolated from UIP lung biopsies. In vivo experiments showed that HGF-expressing BMSC attenuated bleomycin induced pulmonary fibrosis in the rat, indicating a beneficial role of bone marrow derived, HGF secreting stem cells in lung fibrosis.ConclusionsHGF-positive stem cells are present in human fibrotic lung tissue (UIP) and originate from the bone marrow. Since HGF-transfected BMSC reduce bleomycin induced lung fibrosis in the bleomycin lung injury and fibrosis model, we assume that HGF-expressing, bone-marrow derived stem cells in UIP have antifibrotic properties.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a complex pathophysiology and very limited therapeutic options
Hepatocyte growth factor (HGF)-expressing stem cells stain for CXCR4 and originate from the bone marrow, exert multipotent, self-renewing properties in vitro and may have a therapeutic potential when administered into the fibrotic lung as we demonstrate in the bleomycin-induced lung injury and fibrosis model in the rat
HGF-positive cells are present in the fibrotic lung Distinct individual mononuclear cells with positive cytoplasmic staining for HGF were observed in fibrotic areas of usual interstitial pneumonia (UIP) lungs (Figure 1a), many of them in close proximity of the hyperplastic alveolar epithelium that stained positive for c-MET receptor, the receptor for HGF (Figure 1b)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a complex pathophysiology and very limited therapeutic options. It is characterized by severe architectural destruction of the lung tissue leading to fibrotic changes and resulting in impairment of gas exchange and death due to respiratory failure [1,2]. The recent research to understand the pathogenesis and progression of this lethal disease is focused on a dysregulated wound healing response after repeated injury of the alveolar epithelium [3,4]. Pulmonary fibrosis may result from abnormal alveolar wound repair after injury. Stem cells were shown to play a major role in lung injury, repair and fibrosis. Origin and antifibrotic properties of HGF-expressing stem cells in usual interstitial pneumonia
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