HGF Expressing Stem Cells in Usual Interstitial Pneumonia Originate from the Bone Marrow and Are Antifibrotic

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.

Management of Fibrosis: The Mesenchymal Stromal Cells Breakthrough

“…MSCs transfected with an HGF expression plasmid yielded better results than nontransfected MSCs in a pulmonary fibrosis model [72]. The use of recombinant HGF partially reproduced the effects of MSCs in a coculture model with albumin-treated proximal tubular epithelial cells (PTECs) [62].…”

Paracrine factors from mesenchymal stem cells attenuate epithelial injury and lung fibrosis

“…Previous studies have shown that the paracrine factors of MSCs have anti-apoptotic effects in vitro on cardiac cells (27,28), pancreatic β cells (29) and hepatocytes (19). BM-MSCs are known to produce several epithelial specific growth factors, including HGF and KGF (17,18), which have been proven to initiate a variety of biological responses including migration, proliferation, and morpho genesis in AECs (30)(31)(32)(33). Therefore it can be speculated that the protective roles of MSC-CM on AECs may be associated with the epithelial specific growth factors secreted by BM-MSCs and the synergistic effects of these factors.…”

Treatment of silicosis with hepatocyte growth factor-modified autologous bone marrow stromal cells: a non-randomized study with follow-up

“…Our previous research has shown that HGF-modified MSCs (MSCs/HGF), generated by the transfection of an HGF cDNA-containing vector into MSCs, exhibit potent immunosuppressive activity (Bian et al, 2009). In patients with standard interstitial pneumonia, HGF was found to be expressed in the MSCs primarily located in fibrotic areas close to the hyperplastic alveolar epithelium (Gazdhar et al, 2013). Furthermore, HGF-transfected bone marrow MSCs could reduce bleomycin-induced lung fibrosis, suggesting that MSCs/HGF have antifibrotic properties (Gazdhar et al, 2013).…”

“…In patients with standard interstitial pneumonia, HGF was found to be expressed in the MSCs primarily located in fibrotic areas close to the hyperplastic alveolar epithelium (Gazdhar et al, 2013). Furthermore, HGF-transfected bone marrow MSCs could reduce bleomycin-induced lung fibrosis, suggesting that MSCs/HGF have antifibrotic properties (Gazdhar et al, 2013). MSCs/HGF could be sequestered in the radiation-injured lungs, thereby reducing the secretion and expression of pro-inflammatory cytokines and increasing the expression of the anti-inflammatory cytokine IL-10 ( Wang et al, 2013).…”