Telomere Dysfunction and Extracellular Matrix Remodeling

1. Introduction

Telomeres are specialized nucleoprotein structures located at the ends of chromosomes, where the shelterin complex protects chromosome integrity, and in select cell populations, telomerase counteracts repeat loss to maintain telomere length and genomic stability. When telomeres become critically short or structurally uncapped, a persistent DNA-damage response can be engaged, and cell fate can be shifted toward senescence, apoptosis, or loss of regenerative capacity. Telomere dysfunction is thus viewed not merely as a record of a cell’s replicative history but also as an active driver of age-related tissue damage and functional decline [1,2,3].

Fibrosis, in contrast, is characterized by maladaptive tissue repair in which excessive ECM deposition disrupts normal architecture, ultimately driving progressive functional impairment. The ECM is no longer considered a passive scaffold alone, because its composition, organization, crosslinking, and stiffness have all been shown to influence epithelial repair, fibroblast behaviour, immune-cell retention, and tissue mechanics in chronic diseases. Ageing has also been associated with ECM changes that favor a pro-fibrotic microenvironment, while senescent cells further alter ECM turnover through proteases, other ECM-associated proteins, and secreted mediators [4,5] Although telomere dysfunction and fibrosis have traditionally been studied independently, accumulating evidence increasingly highlights their interconnection, making such a separation difficult to maintain. In the lung, disorders of telomere biology represent one of the most well-defined genetic contexts in which fibrotic remodeling occurs, with mutations in telomerase-related genes accounting for a significant proportion of familial pulmonary fibrosis cases [6]. In experimental systems, pulmonary fibrosis has been reproduced either by critically short telomeres or by directly disrupting telomere protection in alveolar type II epithelial cells, suggesting that telomere dysfunction can be sufficient to initiate lung scarring rather than simply accompany it [7,8]. A similar shift has taken place in the kidney. Short and dysfunctional telomeres have been shown to sensitize renal tissue to fibrotic injury, and this link has later been extended by cell-specific models in which telomere dysfunction in renal fibroblasts or tubular epithelial cells has promoted fibrogenic change and kidney fibrosis [9,10,11].

Evidence in the opposite direction has also emerged, although it remains limited. Collagen-dependent signaling has been shown to activate hTERT-associated proliferative responses in vascular smooth muscle cells, while changes in ECM stiffness or compliance have been demonstrated to modulate telomerase-linked senescence programs and influence the pathways through which cells enter proliferative arrest [12,13]. A bidirectional relationship between telomere biology and ECM dynamics therefore needs to be taken into account. In this review, we evaluate the available evidence with particular emphasis on when telomere dysfunction acts upstream of ECM remodeling, when ECM-derived cues are positioned upstream of telomere biology, and which tissues and cell types currently provide the strongest support for each direction of this interaction.

Figure 1. Bidirectional crosstalk between telomere dysfunction and ECM remodeling in tissue degeneration and fibrosis. This schematic illustrates the reciprocal relationship between telomere instability and ECM remodeling, highlighting a self-reinforcing cycle that contributes to impaired tissue regeneration and fibrotic progression. On the left, telomere dysfunction is represented by telomere shortening, shelterin complex loss, telomere uncapping, reduced telomerase activity (TERT), and accumulation of telomere-associated DNA damage, including disruption of protective proteins such as TRF1. These molecular alterations initiate cellular stress responses and genomic instability. Central cellular consequences include cellular senescence, impaired regenerative capacity, inflammatory signaling, and stress pathway activation. Key mediators involved in these shared responses include transforming growth factor-β (TGF-β), cGAS–STING signaling, and adhesion-related inflammatory pathways such as VCAM-1 expression. On the right, downstream extracellular matrix remodeling is characterized by increased collagen deposition (particularly collagen I), fibronectin accumulation, α-smooth muscle actin (α-SMA)–mediated myofibroblast differentiation, matrix stiffening, and progressive tissue scarring. A feedback pathway from ECM remodeling to telomere regulation is illustrated beneath the main flow, demonstrating how matrix stiffness, collagen-rich microenvironments, hyaluronan–RHAMM signaling, and altered mechanotransduction pathways influence cellular proliferation, telomerase activity, and telomere maintenance mechanisms. These feedback signals further promote proliferative arrest and telomere-associated DNA damage, reinforcing telomere dysfunction. Solid arrows indicate well-established mechanistic pathways, whereas dashed arrows represent emerging or partially characterized interactions. Together, this bidirectional model highlights how telomere dysfunction and ECM remodeling function as interconnected drivers of chronic tissue injury, fibrosis, and premature cellular aging. Created in BioRender. https://BioRender.com/ajjcl41.

Figure 1. Bidirectional crosstalk between telomere dysfunction and ECM remodeling in tissue degeneration and fibrosis. This schematic illustrates the reciprocal relationship between telomere instability and ECM remodeling, highlighting a self-reinforcing cycle that contributes to impaired tissue regeneration and fibrotic progression. On the left, telomere dysfunction is represented by telomere shortening, shelterin complex loss, telomere uncapping, reduced telomerase activity (TERT), and accumulation of telomere-associated DNA damage, including disruption of protective proteins such as TRF1. These molecular alterations initiate cellular stress responses and genomic instability. Central cellular consequences include cellular senescence, impaired regenerative capacity, inflammatory signaling, and stress pathway activation. Key mediators involved in these shared responses include transforming growth factor-β (TGF-β), cGAS–STING signaling, and adhesion-related inflammatory pathways such as VCAM-1 expression. On the right, downstream extracellular matrix remodeling is characterized by increased collagen deposition (particularly collagen I), fibronectin accumulation, α-smooth muscle actin (α-SMA)–mediated myofibroblast differentiation, matrix stiffening, and progressive tissue scarring. A feedback pathway from ECM remodeling to telomere regulation is illustrated beneath the main flow, demonstrating how matrix stiffness, collagen-rich microenvironments, hyaluronan–RHAMM signaling, and altered mechanotransduction pathways influence cellular proliferation, telomerase activity, and telomere maintenance mechanisms. These feedback signals further promote proliferative arrest and telomere-associated DNA damage, reinforcing telomere dysfunction. Solid arrows indicate well-established mechanistic pathways, whereas dashed arrows represent emerging or partially characterized interactions. Together, this bidirectional model highlights how telomere dysfunction and ECM remodeling function as interconnected drivers of chronic tissue injury, fibrosis, and premature cellular aging. Created in BioRender. https://BioRender.com/ajjcl41.

Figure 2. Tissue and cell-type map highlighting the strongest evidence across organ systems. This schematic illustrates the distribution of evidence for ECM dysregulation across four representative organ panels: lung, kidney, heart, and vessel/airway. Each panel contains a simplified organ sketch with key cell types and outputs. The lung panel, given the strongest evidence base, emphasizes alveolar type II epithelial cells, fibroblasts, and club/basal cells, with outputs including failed epithelial repair, fibroblast activation, and collagen-rich fibrosis. The kidney panel highlights tubular epithelial cells and renal fibroblasts, associated with fibrogenic change, ECM deposition, and tubulointerstitial fibrosis. The heart panel focuses on atrial tissue and fibroblast-rich interstitium, demonstrating atrial fibrosis and structural remodeling. The vessel/airway panel depicts vascular and airway smooth muscle cells, with phenotypic switching, remodeling, and senescence-associated fibrosis. Evidence markers (G = genetic, M = mechanistic, H = human/translational) are included within each panel to indicate the type and strength of the supporting data. Created in BioRender. https://BioRender.com/h2xvltl.

Figure 2. Tissue and cell-type map highlighting the strongest evidence across organ systems. This schematic illustrates the distribution of evidence for ECM dysregulation across four representative organ panels: lung, kidney, heart, and vessel/airway. Each panel contains a simplified organ sketch with key cell types and outputs. The lung panel, given the strongest evidence base, emphasizes alveolar type II epithelial cells, fibroblasts, and club/basal cells, with outputs including failed epithelial repair, fibroblast activation, and collagen-rich fibrosis. The kidney panel highlights tubular epithelial cells and renal fibroblasts, associated with fibrogenic change, ECM deposition, and tubulointerstitial fibrosis. The heart panel focuses on atrial tissue and fibroblast-rich interstitium, demonstrating atrial fibrosis and structural remodeling. The vessel/airway panel depicts vascular and airway smooth muscle cells, with phenotypic switching, remodeling, and senescence-associated fibrosis. Evidence markers (G = genetic, M = mechanistic, H = human/translational) are included within each panel to indicate the type and strength of the supporting data. Created in BioRender. https://BioRender.com/h2xvltl.

2. Telomere Biology and ECM Biology

Telomere integrity is maintained by a specialized protein complex assembled at chromosome ends, where shelterin components prevent telomeres from being recognized as DNA damage and thereby preserve chromosome stability. Telomere length is shaped by incomplete end replication, nucleolytic processing, oxidative injury, and replication stress, whereas telomerase can compensate for repeat loss in selected stem, progenitor, germline, and activated cell populations. For that reason, telomere dysfunction cannot be reduced to telomere shortening alone, as structurally compromised telomeres may also occur despite preserved length and can still activate a persistent DNA damage response [1,2].

Once telomere protection is lost, checkpoint signaling is engaged and cell fate is often redirected toward senescence, apoptosis, or impaired self-renewal rather than productive tissue repair [1,2]. Among these outcomes, cellular senescence is particularly relevant to tissue remodeling because senescent cells, despite their long-lived arrest, remain metabolically active and can reshape their microenvironment through the secretion of inflammatory mediators, growth factors, ECM components, and matrix-modifying enzymes. Telomere dysfunction therefore occupies a position in which cell-intrinsic mechanisms of genome protection are translated into tissue-level alterations in repair processes and fibrotic scarring [2,5].

ECM, in turn, is a dynamic, tissue-specific network rather than a static structural scaffold. Its major constituents are collagens, elastin and microfibrillar proteins, proteoglycans including hyaluronan, glycoproteins, and associated regulatory proteins, which together define both the biochemical identity and the physical properties of a tissue [14,15]. The architecture of the ECM is continuously reshaped by secretion, assembly, proteolysis, crosslinking, and post-translational modification, so that the composition and mechanics of the ECM are both under active biological control [15]. In disease, these processes can become uncoupled from normal repair and produce an ECM that is denser, stiffer, compositionally altered, and more permissive for persistent fibrogenic signaling [5,15].

Cellular responses to the ECM are mediated primarily through integrins and associated adhesion complexes, which physically and biochemically link extracellular ligands to the actin cytoskeleton, intracellular signaling cascades, and ultimately the nucleus [16]. Through these adhesions, matrix stiffness, ligand density, topography, and force transmission can influence proliferation, differentiation, migration, and survival, while broader tissue-scale mechanical transitions can alter genome activity and cell state [16,17].

Taken together, these fundamental principles render a functional interaction between telomere biology and ECM biology biologically plausible, even prior to consideration of disease-specific evidence. Telomeres regulate a cell’s capacity to sustain division and tolerate genomic stress, whereas the ECM defines the structural and mechanical context in which tissue repair and regeneration occur. A durable repair response would therefore be expected to depend on both systems remaining intact, and persistent remodeling is expected when either one is chronically disturbed [1,15,17].

3. Telomere Dysfunction at Upstream of ECM Remodeling

Direct evidence that primary perturbation of the telomere axis can precede ECM remodeling has been obtained mainly from lung and kidney models, with more recent studies extending this principle to cardiac remodeling. The lung literature is the most well-developed, but it has also made it clear that the biological outcome depends on the cell type in which the telomere pathway is disturbed. In lung fibroblasts, telomerase activity has been shown to limit α-smooth muscle actin expression and inhibit myofibroblast differentiation in vitro [18]. In vivo, however, whole-body or mesenchymal-specific TERT deficiency has been shown to attenuate bleomycin-induced hydroxyproline accumulation, collagen deposition, and fibrotic remodeling, indicating that the telomere axis can actively support ECM remodeling in mesenchymal compartments, even while telomere dysfunction in epithelial compartments drives tissue injury and scarring [19,20].

The strongest pro-fibrotic evidence has emerged from epithelial models. Critically short telomeres, direct telomere uncapping, or loss of telomere protection in alveolar type II cells have each been shown to precede the development of collagen-rich pulmonary fibrosis, rather than merely occurring as a consequence of it [7,8,21]. This principle has further been reinforced by subsequent studies showing that alveolar epithelial type II cell-specific TERT loss heightened susceptibility to bleomycin-induced injury, airway epithelial TRF1 deletion triggered airway-centered remodeling, and telomerase restoration mitigated age-associated pro-fibrotic changes in lung tissue [22,23,24]. Telomere dysfunction in fibroblasts, club cells, or basal cells can alter the fibrotic response to lung injury, although the specific pattern of remodeling still depends on the affected cell compartment and the nature of the injurious stimulus [25]. Comparable causal evidence has now emerged in the kidney, where short or dysfunctional telomeres have been shown to increase susceptibility to folic-acid-induced renal fibrosis in vivo [9]. That observation has been further refined by cell-specific models showing that TRF1 loss in renal fibroblasts or tubular epithelial cells can promote fibrogenic changes, ECM accumulation, and kidney fibrosis [10,11]. Beyond the lungs and kidneys, literature is still more limited, but it has grown enough that evidence can no longer be considered negligible. In silica-associated pulmonary fibrosis, TERF1 deficien [26]. In atrial fibrillation, telomere shortening—observed both in human tissue and in telomerase-deficient mice—has been linked to structural remodeling via VCAM [27] (representative studies are listed in Table 1).

4. Non-Telomeric Upstream Factors Acting Through Telomere Pathways

Evidence supporting the reverse causal direction—where ECM changes influence telomere biology—remains limited, but it is becoming increasingly coherent. In these studies, the initiating signal arises from ECM-derived cues rather than from a primary telomere lesion. Specifically, an extracellular cue, ECM property, paracrine factor, or pharmacologic agent is positioned upstream, and a telomere-associated component has been shown to mediate or modulate the resulting alterations in cell state or tissue remodeling. This pattern has first been demonstrated in lung fibroblasts, where telomerase activity was upregulated by basic fibroblast growth factor and downregulated by interleukin 4 [28]. Under the same conditions, α-smooth muscle actin expression and myofibroblast differentiation have been found to shift in the opposite direction suggesting that telomerase can function as a relay between soluble signaling and fibrogenic cell-state change [18,28]. A related principle has later been reported in vascular smooth muscle cells, where fibrillar collagen-supported proliferation has been shown to depend on hTERT and c-Myc, indicating that a structural ECM ligand can influence growth behavior through telomerase-linked mechanisms [12].

Subsequently, both the composition and mechanical properties of the ECM have been implicated in modulating telomere biology. On hyaluronan-coated surfaces, mesenchymal stem cells are maintained in a slower-cycling state with higher telomerase activity and preserved replicative potential [29]. In nucleus pulposus cells, substrate stiffness can alter senescence together with telomerase activity, and this phenotype is partly alleviated by lysyl oxidase treatment [30]. In WI-38 fibroblasts, ECM softening alters the pathway by which cells enter proliferative arrest, and many of these effects are mitigated by hTERT expression, positioning telomerase-sensitive regulation within a mechanobiological context rather than a purely replicative framework [13].

Non-matrix extracellular signals have also been linked to telomere factors in disease models. In tubular epithelial cells, macrophage-derived exosomal miR-155 has been shown to target TRF1, causing telomere fragility, senescence, fibronectin induction, and α-smooth muscle actin upregulation in a renal injury setting [31]. In vascular smooth muscle cells exposed to oleic acid, metformin increases TERT expression, telomerase activity, and telomere stability while reducing collagen type I, MMP-2, and other markers of phenotypic switching; these effects are attenuated by TERT knockdown [32]. A more direct ECM receptor link has been reported in mouse embryonic fibroblasts, where a truncated RHAMM isoform increases TERT expression, telomerase activity, and selective shelterin transcripts, thereby connecting hyaluronan signaling to telomere maintenance machinery [33]. (representative studies are listed in Table 2).

5. Mechanisms Connecting Telomere Dysfunction to ECM Change

Several routes have been proposed by which telomere dysfunction is converted into ECM change. The broadest route passes through a persistent DNA-damage response and senescence. Telomeric lesions are known to trigger persistent checkpoint activation and a senescence-associated secretory phenotype, and senescent cells, in turn, have been shown to modulate ECM turnover through the secretion of cytokines, growth factors, proteases, and matrix proteins [2,5]. In this way, ECM remodeling can be perpetuated even when the initially damaged cells remain present and are not immediately cleared.

A second route is the failure of epithelial renewal. In the alveolar compartment, telomerase deficiency or telomere dysfunction has been shown to induce progenitor senescence, impair regenerative capacity, and increase susceptibility to bleomycin injury, thereby favoring fibroproliferative repair over effective re-epithelialization [34]. This mechanism is important because fibrosis does not arise solely from ECM-producing cells but also from a persistent failure to restore a functional epithelial barrier.

More direct pro-fibrotic signaling has also been described. In lungs with short telomeres, increased TGF-β1, Smad activation, α-smooth muscle actin, collagen type I, and hydroxyproline have been detected after injurious challenge, placing canonical TGF-β signaling downstream of telomere shortening [35]. In parallel, FBW7-dependent degradation of TPP1 has been shown to trigger telomere uncapping, DNA-damage signaling, cellular senescence, and pulmonary fibrosis under radiation, oxidative stress, or bleomycin exposure [21].

Inflammatory and innate immune routes are now being added to this picture. In kidney tubular cells, macrophage-derived exosomal miR-155 can directly target TRF1 and produce telomere fragility, senescence, fibronectin induction, and α-smooth muscle actin upregulation [31]. In silica-associated pulmonary fibrosis, telomere dysfunction has been linked to cGAS-STING activation together with collagen accumulation and α-smooth muscle actin expression [26]. In aged atrial tissue, a telomere shortening–VCAM-1 axis has been reported, and VCAM-1 inhibition reduces fibrosis and normalizes ECM-related genes such as the gene encoding the α1 chain of type I collagen and the α-smooth muscle actin gene [27] (examples are summarized in Table 3).

6. Tissue Specific and Translational Evidence

The most compelling tissue-level evidence comes from the lung. Integrating human genetics, family-based studies, and tissue analyses have established telomere dysfunction as one of the clearest predisposing factors for fibrotic lung disease, particularly in familial pulmonary fibrosis and related interstitial lung disorders. A central role has been assigned to alveolar type II cells, in which short or dysfunctional telomeres have been linked to defective epithelial maintenance and fibrotic remodeling rather than to a purely incidental ageing signal [6,7,8]. This translational link has been extended by human biopsy material, where short telomeres in alveolar type II cells have been associated with fibrotic parenchymal remodeling in post-COVID lungs [36]. A related, yet more spatially restricted, pattern has been observed in airway disease, where telomere dysfunction in specific epithelial compartments contributes to localized remodeling and fibrosis. In elderly patients with asthma, increased airway fibrosis has been accompanied by elevated telomere-associated foci and other senescence markers in airway smooth muscle cells, indicating that the link between telomere dysfunction and tissue remodeling extends beyond the distal lung parenchyma [37]. However, evidence in the airways remains largely correlative, and causal relationships between telomere dysfunction and localized remodeling have yet to be firmly established.

In the kidney, the evidence has until recently been driven mainly by experimental models, but its tissue resolution has improved substantially. Short or dysfunctional telomeres have been shown to sensitize renal tissue to fibrotic injury, and that signal has since been localized to both renal fibroblasts and tubular epithelial cells by cell-specific TRF1 deletion models [9,10,11]. Human translational evidence is beginning to emerge in the kidney as well. Shorter telomere length in renal tissue has recently been linked to nephrosclerosis and structural decline, whereas leukocyte telomere length has been less predictive of these tissue-level changes [38].

Cardiac evidence has also become more convincing. In patients with atrial fibrillation, shorter telomeres have been associated with adverse left atrial remodeling, an effect further supported by studies in a telomerase-deficient mouse model, where VCAM-1–dependent fibrosis and structural remodeling are increased [27,39]. By contrast, the vascular literature has remained more mechanistic than clinical, with most studies centered on smooth muscle phenotype and atherosclerosis-related remodeling rather than on direct human fibrosis phenotypes [12,32]. Overall, the translational weight is currently highest in lung diseases, increasingly strong in kidney diseases, and emerging in the heart (examples summarized in Table 4).

7. Conclusions

A growing and consistent body of evidence now supports the view that telomere dysfunction can act upstream of ECM remodeling, rather than functioning solely as a passive marker of aging. This conclusion is best supported in the lung and kidney, where short telomeres, telomerase deficiency, or disruption of telomere protection have been shown in cell-specific experimental systems to promote epithelial failure, ECM accumulation, fibrogenic change, and tissue scarring [6,7,8,9,10,11]. In the heart, a comparable connection is beginning to emerge, although the supporting evidence remains more limited [27,39].

At the same time, this relationship cannot be considered strictly unidirectional. ECM composition, stiffness, and matrix-associated signaling have been shown to influence telomerase activity, telomere-linked senescence programs, and the route taken toward proliferative arrest, which indicates that telomere maintenance is responsive to the local extracellular environment [12,13,30,33]. However, evidence for this reverse direction remains limited to fewer systems and disease models, and it has not yet been characterized with the same depth as telomere-driven fibrosis.

Several points appear settled; first, telomere dysfunction should not be understood only as telomere shortening, because uncapping, shelterin loss, and telomere-associated DNA damage can also drive pathological outcomes [1,2]. Second, the biological effect is cell-type dependent. Epithelial telomere dysfunction has generally been linked to failed tissue maintenance and secondary fibrosis, whereas mesenchymal and vascular studies have shown that telomerase-related programs can also directly influence proliferation, phenotype switching, and ECM production [20,32]. Third, the most plausible connecting routes include senescence, defective regeneration, TGF-β signaling, innate immune sensing, and adhesion-related inflammatory signaling [5,26,27,31].

The field continues to exhibit notable gaps: direct causal evidence is concentrated in a few tissues, studies in which ECM-derived cues act upstream of telomere biology remain relatively sparse, and human data are unevenly distributed across organ systems. Thus, further studies are needed in which telomere status, ECM composition and mechanical properties, and cell identity are assessed concurrently within the same experimental model. If such studies are conducted with higher cell-type resolution, it should become possible to distinguish when telomere damage acts as a primary driver of remodeling, when it functions as a secondary amplifier, and when ECM-derived signals feedback to influence telomere maintenance.