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.

Oestrogen retains human periodontal ligament stem cells stemness in long‐term culture

“…42,43 Human telomerase reverse transcriptase elongates and stabilizes telomeres, alleviating replicative senescence and apoptosis. 44 In our study, E2 treatment increased the expression of hTERT in hPDLSCs and prevented cellular senescence (Figures 2 and 5), which suggests that E2 modulate hTERT to maintain hPDLSCs stemness. Sox2, Oct4 and c-Myc are critical stemness-related genes that maintain pluripotency and self-renewal of embryonic stem cells.…”

“…During MSC proliferation in vitro, a decrease in telomere length correlates with the loss of cell viability, suggesting that telomere length and telomerase activity are indispensable for the stemness maintenance . Human telomerase reverse transcriptase elongates and stabilizes telomeres, alleviating replicative senescence and apoptosis . In our study, E2 treatment increased the expression of hTERT in hPDLSCs and prevented cellular senescence (Figures and ), which suggests that E2 modulate hTERT to maintain hPDLSCs stemness.…”

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

“…Numerous studies demonstrated the pro-senescence activity of the Akt signaling pathway [36-38]. However, the anti-senescence activity of the Akt signaling pathway has also been proposed in several types of tissues and cells, such as multipotent mesenchymal stem cells [39]. In our study, GLP-1 suppressed HG/HL-induced Akt activation (Fig.…”

Epigenetic Modifications upon Senescence of Mesenchymal Stem Cells

“…Long-term expansion of MSCs is reflected by telomere attrition, since they have insufficient telomerase activity to overcome the progressive telomere erosion [28]. Supporting these findings, overexpression of hTERT in senescent MSCs partially counteracts replicative senescence [29,30]. On the other hand, long-term cultures of human stem cells, including MSCs, have shown several types of chromosomal abnormalities that could compromise genome integrity and their clinical applicability [31,32].…”