Downregulation of CITED2 contributes to TGFβ-mediated senescence of tendon-derived stem cells
- 382 Downloads
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.
KeywordsTendon-derived stem cells Senescence Cell proliferation Transforming growth factor β2 CITED2
This study was supported by the Fund of Medical Research Foundation of Nanjing Military (ZD04).
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflicts of interest.
- Cashman JD, Eaves AC, Raines EW, Ross R, Eaves CJ (1990) Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-beta. Blood 75:96–101PubMedGoogle Scholar
- Docheva D, Padula D, Popov C, Weishaupt P, Pragert M, Miosge N, Hickel R, Bocker W, Clausen-Schaumann H, Schieker M (2010) Establishment of immortalized periodontal ligament progenitor cell line and its behavioural analysis on smooth and rough titanium surface. Eur Cell Mater 19:228–241CrossRefPubMedGoogle Scholar
- Guerquin MJ, Charvet B, Nourissat G, Havis E, Ronsin O, Bonnin MA, Ruggiu M, Olivera-Martinez I, Robert N, Lu Y, Kadler KE, Baumberger T, Doursounian L, Berenbaum F, Duprez D (2013) Transcription factor EGR1 directs tendon differentiation and promotes tendon repair. J Clin Invest 123:3564–3576CrossRefPubMedPubMedCentralGoogle Scholar
- Kleczko EK, Kim J, Keysar SB, Heasley LR, Eagles JR, Simon M, Marshall ME, Singleton KR, Jimeno A, Tan AC, Heasley LE (2015) An inducible TGF-beta2-TGFbetaR pathway modulates the sensitivity of HNSCC cells to tyrosine kinase inhibitors targeting dominant receptor tyrosine kinases. PLoS One 10:e0123600CrossRefPubMedPubMedCentralGoogle Scholar
- Kohler J, Popov C, Klotz B, Alberton P, Prall WC, Haasters F, Muller-Deubert S, Ebert R, Klein-Hitpass L, Jakob F, Schieker M, Docheva D (2013) Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration. Aging Cell 12:988–999CrossRefPubMedPubMedCentralGoogle Scholar
- Kranc KR, Oliveira DV, Armesilla-Diaz A, Pacheco-Leyva I, Catarina Matias A, Luisa Escapa A, Subramani C, Wheadon H, Trindade M, Nichols J, Kaji K, Enver T, Braganca J (2015) Acute loss of Cited2 impairs nanog expression and decreases self-renewal of mouse embryonic stem cells. Stem Cells 33:699–712CrossRefPubMedGoogle Scholar
- Mueller MB, Fischer M, Zellner J, Berner A, Dienstknecht T, Prantl L, Kujat R, Nerlich M, Tuan RS, Angele P (2010) Hypertrophy in mesenchymal stem cell chondrogenesis: effect of TGF-beta isoforms and chondrogenic conditioning. Cells Tissues Organs 192:158–166CrossRefPubMedPubMedCentralGoogle Scholar