Abstract 13828: Fibroblast Growth Factor-23 Induces Cellular Senescence in Human Mesenchymal Stem Cells From Skeletal Muscle Independently of Klotho Pathway

Abstract

Introduction: Mesenchymal stem cells (MSCs) in skeletal muscle represent a distinct cell population from satellite cells (StCs), and the functional impairment have shown to be associated with ectopic fat formation in muscle tissues. Muscle wasting and/or degeneration are prevalent in heart failure and chronic kidney disease. However, it remains unknown whether such disease condition influences the MSC function and fate. Thus, aim of this study was to investigate effects of fibroblast growth factor (FGF)-23 and angiotensin (ANG)-II, neurohumoral factors related to pathophysiology of cardio-renal syndrome (CRS), on the MSCs in culture system. Methods and Results: MSCs were isolated from human skeletal muscle and cultured with appropriate growth medium. Gene expression analysis demonstrated the enhanced expression of FGF receptors and ANG-II type 1 receptor in the MSCs as compared with the human StCs. Klotho gene was not detected in the two progenitors. The cultured MSCs and StCs were treated with FGF-23 (10ng/ml) and ANG-II (100 nM) for 48 hours. Cell proliferation assay revealed significant decreased cell number in the MSCs treated with FGF-23 but not ANG-II than in the controls (58 % of the controls, p< 0.05). The neurohumoral factors did not affect the cell counts of the StCs. The FGF-23 treated MSCs exhibited the senescent phenotype, as judged by senescence-associated β-galactosidase assay (%senescent cells: 46.5± 11.7 % in the FGF-23 vs. 35.8± 5.8% in the controls, p< 0.05), cell morphology, and increased expression of p53 and p21 in western blot analysis. FGF-23 also augmented intracellular oxidative stress in the MSCs. The mechanisms responsible for the accumulation of reactive oxygen species (ROS) were attributable to increased NADPH oxidase and decreased MnSOD expression in the cells. In histological study, p53-positive senescent MSCs were detected in adipose infiltration area of degenerated gastrocunemius muscle tissues from a CRS patient. Conclusions: Results of this study indicate that FGF-23 induces premature senescence in human MSCs from skeletal muscle via promoting ROS/p53/p21 pathway in klotho-independent action. Interaction of the MSCs with FGF-23 may play a key role in muscle wasting in patients with CRS.