Telomerase Regulation of Myofibroblast Differentiation

Liu, Tianju; Hu, Biao; Chung, Myoung Ja; Ullenbruch, Matt; Jin, Hong; Phan, Sem H.

doi:10.1165/rcmb.2005-0252oc

Cited by 43 publications

(48 citation statements)

References 37 publications

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“…In concordance with our conclusions, it was previously shown that inhibiting telomerase activity or suppressing expression of hTERT caused fibroblast to transdifferentiate into myofibroblasts (Liu et al, 2006). Since telomerase activity is transiently elevated for several days in fibroblasts following tissue damage (Minamino, Mitsialis, & Kourembanas, 2001; Nozaki, Liu, Hatano, Gharaee‐Kermani, & Phan, 2000; Tahara, Sato, Noda, & Ide, 1995), it was suggested that it promotes fibroblast proliferation while antagonizing myofibroblast transdifferentiation during the proliferative stage of tissue repair (Schissel & Layne, 2006).…”

Section: Discussionsupporting

confidence: 93%

“…Since telomerase activity is transiently elevated for several days in fibroblasts following tissue damage (Minamino, Mitsialis, & Kourembanas, 2001; Nozaki, Liu, Hatano, Gharaee‐Kermani, & Phan, 2000; Tahara, Sato, Noda, & Ide, 1995), it was suggested that it promotes fibroblast proliferation while antagonizing myofibroblast transdifferentiation during the proliferative stage of tissue repair (Schissel & Layne, 2006). A decrease in telomerase activity is observed several weeks following tissue damage and during a period in which abundance of myofibroblasts increases (Liu et al, 2006; Liu, Nozaki, & Phan, 2002; Nozaki et al, 2000), raising the possibility that temporally emerging signals in damaged tissue eventually repress hTERT expression, thereby facilitating myofibroblast transdifferentiation. The likely factor that orchestrates all of the events critical for myofibroblast transdifferentiation during tissue repair and wound healing in humans is TGF‐β1, as it negatively regulates transactivation of hTERT expression (Cassar et al, 2016), promotes telomere dysfunction and p53‐dependent expression of αSMA (this study), and activates SMAD3‐dependent expression of αSMA (Hinz, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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“…The BLM-induced telomerase activity is inhibited by treatment of these cells with IL-4 or TGF-β1, which are known to induce expression of α-SMA and myofibroblast differentiation (10). Indeed it has recently been shown that suppression of telomerase activity is closely associated with myofibroblast differentiation, while induction of telomerase by bFGF inhibits α-SMA expression (11). However, the role of telomerase in myofibroblast differentiation remains unclear, nor is it clear whether the induction of telomerase is of importance in the pathogenesis of pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

Liu¹,

Chung²,

Ullenbruch³

et al. 2007

J. Clin. Invest.

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In addition to its well-known expression in the germline and in cells of certain cancers, telomerase activity is induced in lung fibrosis, although its role in this process is unknown. To identify the pathogenetic importance of telomerase in lung fibrosis, we examined the effects of telomerase reverse transcriptase (TERT) deficiency in a murine model of pulmonary injury. TERT-deficient mice showed significantly reduced lung fibrosis following bleomycin (BLM) insult. This was accompanied by a significant reduction in expression of lung α-SMA, a marker of myofibroblast differentiation. Furthermore, lung fibroblasts isolated from BLM-treated TERTdeficient mice showed significantly decreased proliferation and increased apoptosis rates compared with cells isolated from control mice. Transplantation of WT BM into TERT-deficient mice restored BLM-induced lung telomerase activity and fibrosis to WT levels. Conversely, transplantation of BM from TERT-deficient mice into WT recipients resulted in reduced telomerase activity and fibrosis. These findings suggest that induction of telomerase in injured lungs may be caused by BM-derived cells, which appear to play an important role in pulmonary fibrosis. Moreover, TERT induction is associated with increased survival of lung fibroblasts, which favors the development of fibrosis instead of injury resolution.

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“…Interestingly, many observations suggest that the aged lung is more susceptible to injury and fibrosis induced by a variety of stimuli, and this susceptibility may be linked to ageassociated changes in gene expression or genetic polymorphisms such as age-associated telomerase dysfunction [4][5][6][7].…”

mentioning

confidence: 99%

Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy?: Figure 1–

Raghu¹,

Meyer²

2012

Eur Respir J

109

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Telomerase Regulation of Myofibroblast Differentiation

Cited by 43 publications

References 37 publications

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy?: Figure 1–

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