Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

Lin Tong,Yuanlin Song,Qin Wang,Eric J Seeley,Chunxue Bai,Jian Zhou,Jie Liu,Linyi Rong,Jieming Qu,Jue Pan,Xinjun Tang,Xiaodan Zhu

doi:10.1038/srep21642

Abstract

FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

Highlights

Fibroblast growth factor-10 (FGF-10), known as keratinocyte growth factor-2 (KGF-2), has been shown to mediate epithelial-mesenchymal interactions, which are essential to lung development[12,13,14,15,16,17,18]
We demonstrate that lung-resident mesenchymal stem cells (LR-MSCs) can be isolated from the lower respiratory tract of rats pretreated with FGF-10
Intratracheal instillation of FGF-10 (5 mg/kg) three days prior to inflammatory injury was demonstrated to be protective in models of acute lung injury[23,24,25,26,27]

Summary

Introduction

Fibroblast growth factor-10 (FGF-10), known as keratinocyte growth factor-2 (KGF-2), has been shown to mediate epithelial-mesenchymal interactions, which are essential to lung development[12,13,14,15,16,17,18]. FGF-10 is a 20-kDa heparin-binding protein predominantly expressed by mesenchymal cells. It was illustrated that FGF-10 could prevent lung injury after various stresses including bleomycin-induced pulmonary fibrosis[23], high altitude pulmonary edema[24], LPS-induced lung injury[25], mechanical ventilation induced lung injury[26] and ischemia-reperfusion lung injury[27]. We demonstrate that LR-MSCs can be isolated from the lower respiratory tract of rats pretreated with FGF-10. We illustrate that the LR-MSCs isolated from FGF-10 pretreated rats are protective against LPS-induced acute lung injury. We demonstrate for the first time the role of FGF10 in LR-MSCs proliferation, mobilization and the organ specific protective effects against acute lung injury

Methods

Results

Conclusion