Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Abstract

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.

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

“…Senescent cells have been shown to induce paracrine DNA damage and senescence in healthy neighbouring cells via mechanisms involving secretion of SASP factors and increased ROS (Nelson et al , ; Acosta et al , ; Razdan et al , ). In agreement with this, our data showed that keratinocytes surrounding senescent melanocytes also exhibited significantly more telomere damage, providing evidence for a possible bystander effect of senescent melanocytes in human skin in vivo .…”

“…Consistent with our data, previous studies have shown that stimulation of the CXCR3 receptor results in increased ROS generation (Bek et al , ). Moreover, others have also demonstrated that SASP components, notably TGF‐β1, induce paracrine telomere dysfunction in a ROS‐dependent manner (Razdan et al , ). Although the mechanisms that result in enhanced mitochondrial ROS production downstream of CXCR3 signalling have not been fully elucidated, we and others have shown that Akt phosphorylation occurs as a result of CXCR3 activation (Bonacchi et al , ; Shahabuddin et al , ).…”

<p>Repeated intravenous administration of silica nanoparticles induces pulmonary inflammation and collagen accumulation via JAK2/STAT3 and TGF-β/Smad3 pathways in vivo</p>

“…We observed the upregulated protein expression of TGF-β and p-Smad3 in lungs in the SiNP-treated mice (Figure 3D). So in our study, the elevated protein expression of STAT3 and IL-6 contributed to the TGF-β production which promoted the transdifferentiation from fibroblast into myofibroblast so as to accelerate the collagen production in lungs 29…”

“…During the tissue repair and wound healing, fibroblasts are promoted to transdifferentiate into myofibroblasts which are characterized by the de novo expression of αSMA and mainly in charge of production of extracellular matrix components including collagen, fibronectin, and others 29. In our study, we demonstrated that intravenous injection of SiNPs induced moderate increase of αSMA expression and collagen accumulation in lung tissues in the 45 days observation period (Figure 3A and C), indicating that SiNPs was likely to promote the transdifferentiation from fibroblast into myofibroblast thus to accelerate the production of extracellular matrix in lungs.…”

Heparin‐poloxamer hydrogel‐encapsulated rhFGF21 enhances wound healing in diabetic mice

“…However, in the other 3 groups, no obvious skin appendage regeneration was observed. (27,28). Myofibroblasts can secrete large amounts of collagen fibers (29), and the amount can reflect the condition of the granulation tissue.…”