Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells.
Resveratrol is a natural polyphenol antioxidant that has been shown to facilitate osteogenic differentiation. A recent breakthrough has demonstrated that ectopic expression of four genes is sufficient to reprogram murine and human fibroblasts into induced pluripotent stem (iPS) cells. However, the roles of resveratrol in the differentiation and cytoprotection of iPS cells have never been studied. In this study, we showed that, in addition to cardiac cells, neuron-like cells, and adipocytes, mouse iPS cells could differentiate into osteocyte-like cells. Using atomic force microscopy that provided nanoscale resolution, we monitored mechanical properties of living iPS cells during osteogenic differentiation. The intensity of mineralization and stiffness in differentiating iPS significantly increased after 14 days of osteogenic induction. Furthermore, resveratrol was found to facilitate osteogenic differentiation in both iPS and embryonic stem cells, as shown by increased mineralization, up-regulation of osteogenic markers, and decreased elastic modulus. Dexamethasone-induced apoptosis in iPS cell-derived osteocyte-like cells was effectively prevented by pretreatment with resveratrol. Furthermore, resveratrol significantly increased manganese superoxide dismutase expression and intracellular glutathione level, thereby efficiently decreasing dexamethasone-induced reactive oxygen species (ROS) production and cytotoxicity. Transplantation experiments using iPS cell-derived osteocyte-like cells further demonstrated that oral intake of resveratrol could up-regulate osteopontin expression and inhibit teratoma formation in vivo. In sum, resveratrol can facilitate differentiation of iPS cells into osteocyte-like cells, protect these iPS cell-derived osteocyte-like cells from glucocorticoid-induced oxidative damage, and decrease tumorigenicity of iPS cells. These findings implicate roles of resveratrol and iPS cells in the stem cell therapy of orthopedic diseases.
Kao
Chung-Lan
CL
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Peoples Republic of China. clkao@vghtpe.gov.tw
Tai
Lung-Kuo
LK
Chiou
Shih-Hwa
SH
Chen
Yi-Jen
YJ
Lee
Kung-Hsiung
KH
Chou
Shih-Jie
SJ
Chang
Yuh-Lih
YL
Chang
Chia-Ming
CM
Chen
Shih-Jen
SJ
Ku
Hung-Hai
HH
Li
Hsin-Yang
HY
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D003907:Dexamethasone / Q000633:toxicity*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005938:Glucocorticoids / Q000633:toxicity; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology* / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D014161:Transduction, Genetic
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D013267:Stilbenes; D049452:Green Fluorescent Proteins; D003907:Dexamethasone; D000077185:Resveratrol