CITED2
Cbp/p300-interacting transactivator 2 (MSG-related protein 1) (MRG-1) (P35srj) [MRG1]
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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.
MeSH Terms
- Achilles Tendon
- Adult
- Aged
- Biopsy
- Blotting, Western
- Cell Proliferation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p21
- Down-Regulation
- Gene Knockdown Techniques
- Humans
- Proto-Oncogene Proteins c-myc
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
- Repressor Proteins
- Sp1 Transcription Factor
- Stem Cells
- Trans-Activators
- Transforming Growth Factor beta
- Up-Regulation
Keywords
- CITED2
- Cell proliferation
- Senescence
- Tendon-derived stem cells
- Transforming growth factor β2
The transcriptional machinery involved in the transition of an infant from intrauterine to air-breathing life is developmentally regulated, as the fetus and adult manifest differential genetic expression. The low oxygen (O(2)) environment of the mammalian fetus and the increase in O(2) tension that occurs at birth may account for the developmentally regulated alterations in gene expression. We tested the hypothesis that hypoxia-inducible factor 1 (HIF-1) expression, an O(2)-sensitive transcription factor, is developmentally regulated. We found that in fetal pulmonary artery (PA) smooth muscle cells (SMC), fetal HIF-1 protein levels were O(2)-insensitive, whereas in adult PA SMC, hypoxia increased HIF-1 protein expression. Surprisingly, hypoxia increased HIF-1 mRNA expression in fetal, but not in adult, PA SMC. HIF-1 degradation and transcriptional activity is contingent on prolyl- and asparagyl-hydroxylases. To determine whether developmental differences in O(2) sensitivity or expression of these enzymes accounts for the divergence of HIF-1 sensitivity between fetus and adult, we studied the expression of the three most well characterized prolyl-hydroxylases, PHD1, PHD2, and PHD3, and the expression of regulators of HIF-1 transcriptional activity, asparagyl-hydroxylase, factor inhibiting HIF, and the oncogenic factor, CITED2 (CREB-binding protein/p300 interacting transactivator with ED-rich tail). We found that, as in the case of HIF-1, these genes are differentially regulated in the fetus, enabling the mammalian fetus to thrive in the low O(2) tension intrauterine environment even while rendering a newborn infant uniquely well adapted to respond to the acute increase in O(2) tension that occurs at birth.
MeSH Terms
- Aging
- Animals
- Cells, Cultured
- Gene Expression Regulation, Developmental
- Hypoxia-Inducible Factor 1
- Lung
- Muscle, Smooth, Vascular
- Myocytes, Smooth Muscle
- Procollagen-Proline Dioxygenase
- RNA, Messenger
- Repressor Proteins
- Sheep