title: Expression of human telomerase reverse transcriptase mediates the senescence of mesenchymal stem cells through the PI3K/AKT signaling pathway.
abstract: Multipotent mesenchymal stem cells (MSCs) are widely used as seed cells in studies of tissue engineering and regenerative medicine; however, their clinical application is limited due to replicative senescence. It has been demonstrated that telomerase expression extends the lifespan and maintains the bone-forming ability of MSCs; however, the detailed role and the underlying molecular mechanisms in MSCs remain largely unknown. In the present study, we found that senescence was associated with human telomerase reverse transcriptase (hTERT) expression, and telomere length and telomerase activity. We established a short interfering RNA (siRNA) targeting hTERT and a gene expression vector carrying hTERT and transfected these into the MSCs to investigate the detailed role and the underlying molecular mechanisms of action of hTERT in MSCs. We found that the downregulation of hTERT by siRNA markedly decreased telomere length and telomerase activity in the MSCs, whereas the overexpression of hTERT increased telomere length and telomerase activity in the MSCs. The downregulation of hTERT inhibited cell proliferation and promoted the senescence and apoptosis of MSCs, whereas the upregulation of hTERT increased cell proliferation and decreased the senescence and apoptosis of MSCs. Of note, we also found that the activation of the PI3K/AKT signaling pathway was mediated by hTERT and that blocking this pathway using LY294002 inhibited hTERT expression, induced senescence and decreased the proliferation of MSCs. These findings reveal a previously unknown regulatory mechanism of hTERT, indicating that hTERT mediates the senescence of MSCs through the PI3K/AKT signaling pathway.
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Norman Bethune College of Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Xue-Yao
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Yu
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Zhai
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Ying-Ai
authors.initials: YA
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D016922:Cellular Senescence; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase