The influence of fibroblast growth factor 2 on the senescence of human adipose-derived mesenchymal stem cells during long-term culture
Journal
Stem Cells Translational Medicine
Date Issued
2019
Author(s)
Abstract
Adipose-derived mesenchymal stem cells (ASCs) exhibit great potential in regenerative medicine, and in vitro expansion is frequently necessary to obtain a sufficient number of ASCs for clinical use. Fibroblast growth factor 2 (FGF2) is a common supplement in the ASC culture medium to enhance cell proliferation. To achieve clinical applicability of ASC-based products, prolonged culture of ASCs is sometimes required to obtain sufficient quantity of ASCs. However, the effect of FGF2 on ASCs during prolonged culture has not been previously determined. In this study, ASCs were subjected to prolonged in vitro culture with or without FGF2. FGF2 maintained the small cell morphology and expedited proliferation kinetics in early ASC passages. After prolonged in vitro expansion, FGF2-treated ASCs exhibited increased cell size, arrested cell proliferation, and increased cellular senescence relative to the control ASCs. We observed an upregulation of FGFR1c and enhanced expression of downstream STAT3 in the initial passages of FGF2-treated ASCs. The application of an FGFR1 or STAT3 inhibitor effectively blocked the enhanced proliferation of ASCs induced by FGF2 treatment. FGFR1c upregulation and enhanced STAT3 expression were lost in the later passages of FGF2-treated ASCs, suggesting that the continuous stimulation of FGF2 becomes ineffective because of the refractory downstream FGFR1 and the STAT3 signaling pathway. In addition, no evidence of tumorigenicity was noted in vitro and in vivo after prolonged expansion of FGF2-cultured ASCs. Our data indicate that ASCs have evolved a STAT3-dependent response to continuous FGF2 stimulation which promotes the initial expansion but limits their long-term proliferation. ? 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
SDGs
Other Subjects
fibroblast growth factor; fibroblast growth factor 2; STAT3 protein; fibroblast growth factor 2; fibroblast growth factor receptor 1; mitogen activated protein kinase; STAT3 protein; adipose derived stem cell; adult; Article; bone development; carcinogenicity; cell cycle; cell growth; cell isolation; cell proliferation; cell size; cell structure; cell surface; colony forming cell; controlled study; DNA synthesis; female; fibroblast; flow cytometry; gene expression; gene expression level; human; human cell; human cell culture; immunophenotyping; mouse; nonhuman; phase contrast microscopy; protein expression; protein phosphorylation; real time polymerase chain reaction; RNA isolation; senescence; signal transduction; stem cell culture; upregulation; Western blotting; carcinogenesis; cell aging; cell culture; cell differentiation; cell shape; cytology; drug effect; genetics; mesenchymal stem cell; metabolism; middle aged; pathology; phosphorylation; risk factor; Adult; Carcinogenesis; Cell Differentiation; Cell Proliferation; Cell Shape; Cells, Cultured; Cellular Senescence; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblast Growth Factor 2; Humans; Immunophenotyping; Mesenchymal Stem Cells; Middle Aged; Phosphorylation; Receptor, Fibroblast Growth Factor, Type 1; Risk Factors; STAT3 Transcription Factor; Up-Regulation
Publisher
John Wiley and Sons Ltd.
Type
journal article