title: Downregulation of CITED2 contributes to TGFβ-mediated senescence of tendon-derived stem cells.
abstract: Tendon-derived stem cells (TDSCs) are multipotent adult stem cells with potential applications in tendon and tendon-bone junction repair. However, cellular characteristics change during in vitro passaging. Therefore, elucidation of the molecular and cellular mechanisms of tendon aging will be essential for the development of TDSC-based therapies. The aim of this study is to investigate the effect of CITED2, a nuclear regulator and transforming growth factor β2 (TGFβ2) on TDSC proliferation and senescence by comparing cells derived from Achilles tendon biopsies of young individuals (Y-TDSC) with those of older patients (O-TDSC). Our results showed that CITED2 mRNA and protein expression levels were significantly higher in Y-TDSCs than in O-TDSCs and O-TDSCs displayed decreased proliferation and increased senescence compared with Y-TDSCs. Furthermore, high levels of CITED2 protein expression in Y-TDSCs correlated with the downregulation of SP1 and p21 and the upregulation of MYC, potentially indicating the mechanism by which CITED2 upregulates TDSC proliferation. TGFβ2 was found to downregulate the expression of the CITED2 gene and knockdown of CITED2 abolished the effect of TGFβ2 on TDSC proliferation and senescence. Thus, the downregulation of CITED2 contributes to TGFβ-mediated senescence providing an insight into the molecular and cellular mechanisms that contribute to tendon aging and degeneration. Our findings may aid the development of cell-based therapies for tendon repair.
authors.affiliation: Department of Orthopedics, 101st Hospital of PLA, No. 101 North Xingyuan Road, Beitang District, Wuxi, Jiangsu, 214000, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Orthopedics, 101st Hospital of PLA, No. 101 North Xingyuan Road, Beitang District, Wuxi, Jiangsu, 214000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
authors.forename: Kanglai
authors.initials: K
authors.lastname: Tang
authors.affiliation: Department of Orthopedics, 101st Hospital of PLA, No. 101 North Xingyuan Road, Beitang District, Wuxi, Jiangsu, 214000, China. luoyuchun101@163.com.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Orthopedics, 101st Hospital of PLA, No. 101 North Xingyuan Road, Beitang District, Wuxi, Jiangsu, 214000, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
authors.forename: Wan
authors.initials: W
authors.lastname: Chen
mesh_terms: D000125:Achilles Tendon / Q000166:cytology*; D000328:Adult; D000368:Aged; D001706:Biopsy; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C486381:CITED2 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta
keywords: CITED2; Cell proliferation; Senescence; Tendon-derived stem cells; Transforming growth factor β2