CoChat
Sign Up
Cited by 2,045Wound Healing and TreatmentsTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA

Open access
Demaria, Marco, Ohtani, Naoko, Youssef, Sameh A., Rodier, Francis, Toussaint, Wendy, Mitchell, James R., Laberge, Remi-Martin, Vijg, Jan +6 more·2014·Developmental Cell
DOI 10.1016/j.devcel.2014.11.012PMC PMC4349629
Open this paper in CoChat — free accountOpen PDF

Abstract

Cellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the physiological role(s) of the complex senescent phenotype, we generated a mouse model in which senescent cells can be visualized and eliminated in living animals. We show that senescent fibroblasts and endothelial cells appear very early in response to a cutaneous wound, where they accelerate wound closure by inducing myofibroblast differentiation through the secretion of platelet-derived growth factor AA (PDGF-AA). In two mouse models, topical treatment of senescence-free wounds with recombinant PDGF-AA rescued the delayed wound closure and lack of myofibroblast differentiation. These findings define a beneficial role for the SASP in tissue repair and help to explain why the SASP evolved.

Integrity signals

Registry

Crossref · 10.1016/j.devcel.2014.11.012

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

15 of 32 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Tissue repair and wound healing are impaired in old individuals.

    “Moreover, tissue repair and wound healing are impaired in old individuals (Guo and Dipietro, 2010)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Guo and Dipietro, 2010 source

      The Age subsection under Systemic Factors That Influence Healing calls increased age a major risk factor for impaired wound healing and describes age-related delays in repair processes. It also specifies that, in healthy older adults, aging delays wound healing without impairing the quality of healing; the unqualified claim misses that distinction. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Senescent stromal cells help resolve excessive fibrosis after skin or liver injury.

    “Senescent stromal cells were shown to help resolve excessive fibrosis after skin or liver injury (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Jun and Lau, 2010 source
    • cites Krizhanovsky et al., 2008 source
  • Premisecitation

    Cultured MEFs induced to senesce by IR robustly induced IL-6 7-10 days after stimulation.

    “although it was robustly induced 7–10 days after cultured MEFs were stimulated to senesce by IR (Coppé et al., 2008)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Coppé et al., 2008 source

      In the human-fibroblast results (Fig. 1), the paper reports that IL-6 was detectable in senescent cells and that irradiation-induced cells developed a robust secretory phenotype 4–7 days after exposure. Those results concern human fibroblasts, not cultured mouse embryonic fibroblasts (MEFs), and do not establish the claimed 7–10-day timing for IL-6 in MEFs. The indexed passages provide no page numbers. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Findingown data

    Senescent fibroblasts and endothelial cells appear very early after cutaneous wounding.

    “We show that senescent fibroblasts and endothelial cells appear very early in response to a cutaneous wound”
    • Also stated in: § INTRODUCTION · plain
      “Here we show that senescent fibroblasts and endothelial cells appear at wound sites a few days after skin injury.”
    Quote in the paperSubstantial claim
  • Findingown data

    p16/p21 double knockout mice show delayed wound healing compared with WT mice.

    “Similar to our findings using GCV-treated p16-3MR mice, p16/p21 DKO mice showed delayed wound healing compared with WT counterparts (Figure 3I).”
    Quote in the paperSubstantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    GCV is converted by HSV-TK into a toxic DNA chain terminator; in nondividing senescent cells, GCV fragments mitochondrial DNA, causing apoptosis.

    “HSV-TK converts GCV into a toxic DNA chain terminator; in nondividing senescent cells, GCV fragments mitochondrial DNA, causing death by apoptosis (Laberge et al., 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Laberge et al., 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Senescent cells were recently detected during embryogenesis, where they appear to play a nonessential role in optimizing the development of certain embryonic structures.

    “Of possible relevance to this puzzle, senescent cells were recently detected during embryogenesis, where they appear to play a nonessential role in optimizing the development of certain embryonic structures (Muñoz-Espín et al., 2013; Storer et al., 2013).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Muñoz-Espín et al., 2013 source
    • cites Storer et al., 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most senescent cells express p16INK4a.

    “Although there are no strictly specific senescence markers, most senescent cells express the tumor suppressor p16INK4a (Ohtani et al., 2004)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ohtani et al., 2004 source

      The “p16 INK4a-RB pathway in human cancer” section (p. 4) says p16INK4a expression is significantly induced during cellular senescence and that it accumulates in human and rodent senescent cells. It does not establish that most senescent cells express it; the majority claim goes beyond the passage. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Matrix metalloproteinases that comprise the SASP were proposed to facilitate tissue repair by promoting collagen degradation, thereby limiting fibrosis.

    “and the matrix metalloproteinases that comprise the SASP (Coppé et al., 2008, 2010b) were proposed to facilitate tissue repair by promoting collagen degradation, thereby limiting fibrosis (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Coppé et al., 2008, 2010b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Jun and Lau, 2010 source
      Experimental — accuracy not yet measured
    • cites Krizhanovsky et al., 2008 source
      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    p16INK4a increases with age and is a robust senescence marker in numerous mouse and human tissues, often coinciding with SA-β-gal activity.

    “p16INK4a also increases with age and is a robust senescence marker in numerous mouse and human tissues (Krishnamurthy et al., 2004; Ressler et al., 2006), often coinciding with another prominent senescence marker, senescence-associated beta-galactosidase (SA-β-gal) activity (Dimri et al., 1995).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Krishnamurthy et al., 2004 source

      The Expression of Ink4a/Arf in vivo section reports that p16INK4a increases with age across varied mouse cell types, and the caloric-restriction section reports overlapping p16INK4a expression and SA-β-gal activity in aging rodent kidney. Table 1 compares the mouse findings with published human tissue staining, but this paper does not establish age-related increases across numerous human tissues. It also proposes p16INK4a as a robust marker of aging rather than demonstrating it as a robust senescence marker across all those tissues. The citing sentence separately attributes the SA-β-gal-marker point to Dimri et al. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Ressler et al., 2006 source
    • cites Dimri et al., 1995 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activation of CCN1 was shown to induce senescence during skin and liver repair.

    “activation of the matricellular protein CCN1 was shown to induce senescence during skin and liver repair (Jun and Lau, 2010; Kim et al., 2013).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Jun and Lau, 2010 source
    • cites Kim et al., 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Recent reports showed a beneficial role for the SASP during embryonic development and in limiting fibrosis after tissue injury.

    “recent reports showed a beneficial role for the SASP during embryonic development (Muñoz-Espín et al., 2013; Storer et al., 2013) and a role in limiting fibrosis after tissue injury (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Muñoz-Espín et al., 2013 source

      The Clearance of Senescent Cells and Compensatory Mechanisms section (page unavailable) reports that developmental senescence triggers macrophage-mediated elimination of embryonic mesonephric tubules. The Introduction describes how the SASP can promote tissue remodeling, but the paper does not establish that the SASP specifically causes the beneficial developmental effects. The fibrosis clause is cited to other papers in the citing sentence, not to Muñoz-Espín et al. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Storer et al., 2013 source
    • cites Jun and Lau, 2010 source

  • May combine two claims.

    Findingown data

    GCV selectively kills senescent p16-3MR MEFs and shows no significant toxicity in nonsenescent p16-3MR or wild-type cells.

    “Finally, GCV selectively killed senescent p16-3MR MEFs and showed no significant toxicity in nonsenescent p16-3MR or wild-type (WT) cells (Figure 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GCV treatment of old (20-24 months) p16-3MR mice eliminates senescent cells, as shown by reduced total body luminescence and reduced luminescence, SA-β-gal staining, and p16 mRNA in visceral fat.

    “GCV treatment of old (20–24 months) mice efficiently eliminated senescent cells as determined by reduced total body luminescence (Figures 2C and S2E) and reduced luminescence, SA-β-gal staining, and p16INK4a mRNA levels in biopsies of visceral fat (Figures 2D–2F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Male p16-3MR mice show a similar transient induction of senescent cells after wounding but with kinetics slower by 2-3 days, consistent with their slower wound closure.

    “Male animals showed a similar transient induction of senescent cells but with kinetics that were slower by 2–3 days, consistent with their slower wound closure (Figure S3A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Irradiation-induced senescence in p16-3MR MEFs is accompanied by increased p16 protein and a set of marker changes including decreased DNA synthesis, increased SA-β-gal, increased p16, p21, IL-6, and MMP-3 mRNAs, and decreased laminB1 mRNA.

    “As expected, endogenous p16INK4a protein levels increased, peaking ~10 days after IR (Figure S1A available online). We confirmed senescence by decreased DNA synthesis, increased SA-β-gal activity (Figure S1B), increased levels of mRNAs encoding p16INK4a, p21, and the SASP factors interleukin-6 (IL-6) and MMP-3, and decreased levels of the mRNA encoding laminB1 (Freund et al., 2012) (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Senescent p16-3MR MEFs express mRFP and have increased luciferase activity.

    “Further, senescent p16-3MR MEFs expressed mRFP by immunostaining (Figures 1C and S1B), with a concomitant increase in luciferase activity (Figure 1D).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    A fraction (2.8%) of senescent RFP+ fibroblasts is positive for smooth muscle actin (SMA), a myofibroblast marker.

    “A fraction of senescent (RFP+) fibroblasts (2.8%) was also positive for a marker of myofibroblasts (smooth muscle actin [SMA]), as reported (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    GCV treatment of irradiated p16-3MR mice reduces total body luminescence and senescence-associated gene expression, but not IL-5, in fat, kidneys, and lungs.

    “Importantly, GCV treatment of irradiated p16-3MR mice markedly reduced total body luminescence and senescence-associated gene expression, but not IL-5 expression, in fat, kidneys and lungs (Figures 2A, 2B, S2B, and S2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    RFP+ cells from wounds are positive for fibroblast and endothelial markers and negative for keratinocyte markers.

    “Notably, RFP+ cells were positive for markers of fibroblasts and endothelial cells (which were highly enriched in the senescent population), but negative for keratinocyte markers (Figure 4D), indicating that fibroblasts and endothelial cells, but not the epidermal epithelial cells, are the predominant cell types that become senescent in response to skin injury.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Senescent cells secreted significantly more PDGF-AA than nonsenescent cells, but not more PDGF-AB or PDGF-BB.

    “These senescent cells also secreted significantly higher levels of PDGF-AA, but not PDGF-AB or PDGF-BB, relative to nonsenescent cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wound gaps of control, but not GCV-treated, mice show p21+ cells, which are mostly fibroblasts and capillary endothelial cells based on morphology.

    “Wound gaps of control, but not GCV-treated, mice showed p21+ cells, which were mostly fibroblasts and capillary endothelial cells (based on morphology), confirming that senescent cells present in the wounds are mostly mesenchymal/fibroblastic and endothelial cells (Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On day 6 after injury, PBS-treated wounds show significant wound contraction and marked re-epithelialization.

    “On day 6, the wounds of PBS-treated mice showed significant wound contraction and marked re-epithelialization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The p16-3MR mouse model allows senescent cells to be detected in living animals, isolated from tissues, and eliminated by GCV.

    “we created a mouse model (p16-3MR) in which senescent cells can be detected in living animals, isolated from tissues, and eliminated upon treatment with an otherwise ineffective drug.”
    • Also stated in: § The p16-3MR Mouse Model · boosted
      “Together, these findings show that p16-3MR transgenic mice accurately report the presence of senescent cells through luminescence and allow their elimination by GCV.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RFP+ cells from wounds have moderately elevated levels of PAI-1, CCL5, and CCL2, but not IL-6 or TGF-β.

    “RFP+ cells also had moderately elevated levels of the SASP factors PAI-1, CCL5, and CCL2, but not other SASP factors, such as IL-6 or transforming growth factor β (Figure 5A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Visceral fat from young p16-3MR mice shows no difference in luminescence, SA-β-gal, or p16 mRNA upon GCV treatment.

    “Notably, visceral fat from young mice showed no difference in luminescence, SA-β-gal, or p16INK4a mRNA levels upon GCV treatment (Figures 2D–2F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Wound biopsies from GCV-treated mice have significantly less MMP-2 but significantly more MMP-10 and MMP-13 than vehicle-treated mice.

    “Analysis of the levels of mRNAs encoding different matrix metalloproteinases revealed that wound biopsies had significantly less MMP-2 but significantly more MMP-10 and MMP-13 when isolated from mice treated with GCV compared with vehicle-treated mice (Figure S4F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In irradiated p16-3MR mice, IR induces luminescence in living animals and isolated visceral fat, kidneys, and lungs, and increases mRNAs for p16, 3MR, IL-6, and MMP-3, but not IL-5.

    “IR induced luminescence in living animals (Figure 2A) and in isolated visceral fat, kidneys, and lungs (Figure S2A). These tissues also showed increased levels of mRNAs encoding p16INK4a, 3MR (mRFP), and the SASP factors IL-6 and MMP-3, but not the non-SASP factor IL-5 (Figures 2B, S2B, and S2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    RFP+ cells isolated from wounds 6 days after injury express very high levels of PDGF-A, not previously identified as a SASP factor, and VEGF, a known SASP component.

    “Compared with RFP− cells, RFP+ cells expressed very high levels of PDGF-A, not previously identified as a SASP factor, and VEGF, a known SASP component (Coppé et al., 2006) (Figure 5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After wounding, senescent cells are transiently detected at the injury site, with variable presence at day 2, significant appearance at day 3, peak around day 6, and return to basal levels between days 9 and 12 in young female p16-3MR mice.

    “In young female p16-3MR animals, senescent cells were variable 2 days after wounding but significantly apparent 3 days after wounding; senescent cells peaked ~6 days after wounding and then returned to barely detectable basal levels between 9 and 12 days after wounding (Figures 3A and 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On day 6, GCV-treated wounds show wide epithelial and dermal edges, necrotic fibrinoid and cellular debris in the gap, reduced angiogenesis and inflammation, paucity of collagen deposition, and poor granulation tissue.

    “At this time, wounds of GCV-treated mice, in contrast, showed wide epithelial and dermal edges and the wound gap was filled with necrotic fibrinoid and cellular debris, with much reduced angiogenesis and inflammation, a paucity of collagen deposition, and poor formation of granulation tissue as revealed by trichrome staining (Figures 4A and 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wounds with or without senescent cells had comparable levels of Ki67+ cells, arguing against a major effect of GCV on cell proliferation.

    “Importantly, wounds with or without senescent cells showed comparable levels of Ki67+ cells, arguing against a major effect of GCV on cell proliferation (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wounding induces senescence in resident fibroblasts and primarily endothelial cells.

    “Our data indicate that wounding induces senescence in resident fibroblasts and primarily endothelial cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    CCN1 also induced IL-6 in primary cultured cells.

    “but it also induced IL-6”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Senescent cells were present only transiently during tissue repair, unlike their persistent presence in aged or chronically damaged tissues.

    “Notably, senescent cells were present only transiently during tissue repair, in contrast to the persistent presence of senescent cells in aged or chronically damaged tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The SASP is a dynamic phenotype whose effects can vary with the interval during which senescent cells are present.

    “These data suggest the SASP is a dynamic phenotype and that it can have different effects depending on the interval during which senescent cells are present.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PDGF-AA is a SASP factor expressed by senescent cells that populate wounds.

    “Thus, PDGF-AA is a SASP factor that is expressed by the senescent cells that populate wounds.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Myofibroblasts are thought to arise from conversion of wound site fibroblasts into a myofibroblastic phenotype.

    “which are thought to arise from the conversion of wound site fibroblasts into a myofibroblastic phenotype (Gabbiani, 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gabbiani, 2003 source

  • May combine two claims.

    Interpretationown data

    Apoptosis is only slightly but not significantly increased in the poorly formed granulation tissue of GCV-treated wounds, arguing against a significant bystander effect of GCV.

    “Apoptosis was only slightly but not significantly increased in the poorly formed granulation tissue (Figure S4A), most likely reflecting the death of senescent cells and arguing against a significant bystander effect of GCV.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PDGF-A is mitogenic for mesenchymal cells expressing PDGF-Rα, plays an important role in granulation tissue formation, and is crucial for myofibroblast differentiation/maturation during wound repair.

    “PDGF-A is also mitogenic for cells of mesenchymal origin that express the receptor PDGF-Rα, plays an important role in the formation of granulation tissue, and is crucial for myofibroblast differentiation/maturation during wound repair (Betsholtz, 2004; Boström et al., 1996; Ostman and Heldin, 2001; Pho et al., 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Betsholtz, 2004 source
    • cites Boström et al., 1996 source
    • cites Ostman and Heldin, 2001

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Senescent cells in wounds likely secrete less collagen and express higher levels of certain MMPs, supporting a role for senescent cells in limiting fibrosis.

    “Thus, the senescent cells in wounds likely secreted less collagen and expressed higher levels of certain MMPs, supporting our results with picrosirius red staining (Figure S4C) and a role for senescent cells in limiting fibrosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PDGF-A is expressed by several cell types during tissue repair and is generally reduced in mice with impaired wound healing.

    “PDGF-A is expressed by several cell types during tissue repair and is generally reduced in mice with impaired wound healing (Beer et al., 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Beer et al., 1997 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Wound closure occurs during the proliferation phase as a consequence of wound contraction, due primarily to formation of granulation tissue and induction of myofibroblasts.

    “In this tissue, wound closure occurs during the proliferation phase as a consequence of wound contraction (Midwood et al., 2004), which is due primarily to the formation of a newly synthesized granulation tissue and induction of specialized contractile fibroblasts termed myofibroblasts (Tomasek et al., 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Midwood et al., 2004 source
    • cites Tomasek et al., 2002 source

  • May combine two claims.

    Interpretationown data

    Senescent cells facilitate cutaneous wound repair and their absence significantly retards the kinetics of wound closure.

    “These data indicate that senescent cells facilitate cutaneous wound repair and that their absence significantly retards the kinetics of wound closure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The findings define a beneficial role for the SASP in tissue repair and help explain why the SASP evolved.

    “These findings define a beneficial role for the SASP in tissue repair and help to explain why the SASP evolved.”
    • Also stated in: § INTRODUCTION · plain
      “These data support a positive role for senescent cells during tissue repair and help to explain why the SASP evolved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Senescent cell-derived PDGF-AA is necessary and sufficient for timely wound closure in WT mice.

    “indicating that senescent cell-derived PDGF-AA is necessary and sufficient for timely wound closure in WT mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Senescence induction entailed secretion of PDGF-AA by senescent cells, which promotes myofibroblast differentiation, optimal granulation tissue formation, and ultimately the kinetics of wound closure.

    “This senescence induction entailed the secretion of PDGF-AA by the senescent cells, which promotes myofibroblast differentiation, optimal granulation tissue formation, and ultimately the kinetics of wound closure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PDGF-AA is an early SASP factor produced by senescent cells in wound sites, which optimizes myofibroblast differentiation and hence the kinetics of wound closure.

    “Together, these findings identify PDGF-AA as an early SASP factor produced by senescent cells in wound sites, which optimizes myofibroblast differentiation and hence the kinetics of wound closure.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Treatment with GCV in p16-3MR mice selectively removes senescent cells from wounded skin without affecting other cell types.
    • Rests on an assumption: The p16/p21 double-knockout mouse model lacks senescent cells after wounding.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Senescent cells accumulate with age and are thought to contribute to age-related diseases through the SASP.

    “Senescent cells accumulate with age and are thought to contribute to age-related diseases through the SASP (Coppé et al., 2008, 2010a; Krtolica et al., 2001; Parrinello et al., 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Coppé et al., 2008, 2010a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Krtolica et al., 2001 source
    • cites Parrinello et al., 2005 source

  • May combine two claims.

    Interpretationown data

    Elimination of senescent cells by GCV depleted wound sites of myofibroblasts, consistent with slower wound healing in GCV-treated p16-3MR mice.

    “Thus, elimination of senescent cells by GCV depleted wound sites of myofibroblasts, consistent with the slower wound healing shown by GCV-treated p16-3MR mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Treatment with GCV in p16-3MR mice selectively removes senescent cells from wounded skin without affecting other cell types.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Senescence was confirmed by bromodeoxyuridine labeling and SA-βgal activity.

    “Senescence was confirmed by bromodeoxyuridine labeling and SA-βgal activity (Dimri et al., 1995) using commercial kits”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dimri et al., 1995 source

  • May combine two claims.

    Interpretationown data

    The results demonstrate a positive role for senescent cells and the SASP in tissue repair.

    “the results presented here unambiguously demonstrate a positive role for senescent cells and the SASP in tissue repair.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mouse wound-healing model used here is representative of tissue repair in general.
47 of 47

  • The paper relies on this without support.

    Treatment with GCV in p16-3MR mice selectively removes senescent cells from wounded skin without affecting other cell types.

    “Thus, elimination of senescent cells by GCV depleted wound sites of myofibroblasts”

  • The paper relies on this without support.

    The p16/p21 double-knockout mouse model lacks senescent cells after wounding.

    “Similar to GCV-treated p16-3MR mice, wounds in p16/p21 DKO mice showed significantly fewer myofibroblasts after wounding compared with WT mice”

  • The paper relies on this without support.

    The mouse wound-healing model used here is representative of tissue repair in general.

    “the results presented here unambiguously demonstrate a positive role for senescent cells and the SASP in tissue repair.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the other 30-70% of senescent cells, the SASP appears to contain growth and regenerative factors, may cause less apoptosis, tissue destruction, and fibrosis, and can contribute to tissue repair via factors such as VEGF-A and PDGF-AA.

    “In the other 30–70% of senescent cells, the SASP appears to comprise growth and other regenerative factors, potentially causing less apoptosis, tissue destruction and fibrosis than proapoptotic, pro-inflammatory senescent cells and can even contribute to tissue repair (for example, through the growth factors VEGF-A and PDGF-AA)61,65.”

    From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [65]

    The Discussion (page unavailable) reports that senescent cells accelerate cutaneous wound healing through PDGF-AA secretion and help restrain fibrosis. The Results (page unavailable) also report increased VEGF mRNA in wounds, but do not establish VEGF-A as a repair mechanism. The paper does not support the 30–70% estimate or the comparison involving less apoptosis and tissue destruction. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Transient senescent cells can have beneficial functions: their SASPs can orchestrate tissue remodeling, induce immune responses during infection or injury, promote parturition via placental senescent cells, and attract immune cells to clear pro-inflammatory senescent cells.

    “If senescent cells are present transiently, beneficial functions of both the proapoptotic and pro-growth types of SASP can orchestrate tissue remodeling”

    From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [65]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Senescent cells are not always harmful; they have important functions in wound healing and childbirth.

    “Note that Sncs are not always pathological. They play important roles in, for example, wound healing and parturition (23).”

    From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [23]

    The Introduction and Discussion (page unavailable) report that senescent cells promote cutaneous wound healing, supporting the point that they are not always harmful. Our copy does not address a role in parturition (searched: parturition, childbirth), so that example is unsupported by this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • There are numerous distinct cell types within the lung required for functional substructures, and there is heterogeneity of senescence phenotypes across lung cell types.

    “Like many other tissues, there are numerous distinct cell types within the lung required for creating functional substructures; thus, there is also heterogeneity of senescence phenotypes across lung cell types64–70 (Fig. 2 C).”

    From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [65]

    The Results section on senescent endothelial and mesenchymal cells reports that fibroblasts and endothelial cells, but not epidermal cells, predominated among senescent cells after skin injury. This supports cell-type differences in senescence in skin, but the paper does not establish the claimed heterogeneity across lung cell types or discuss their functional substructures. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • 18-month-old AP-treated ATTAC mice repaired cutaneous wounds when drug administration was suspended during healing.

    “Consistent with a beneficial role of senescent cells only for the duration of wound repair 6 - 8 , 18-month-old AP-treated ATTAC mice repaired cutaneous wounds when drug administration was suspended during healing (Extended Data Fig. 10ac).”

    From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [8]

    The Results section ('Elimination of Senescent Cells Delays Cutaneous Wound Healing'; page unavailable) reports that senescent cells facilitate cutaneous wound repair. The Experimental Procedures ('Mice'; page unavailable) describe p16-3MR mice treated with GCV, not 18-month-old ATTAC mice treated with AP. Our copy does not report wound repair after AP administration was suspended during healing. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Four-day analysis conflicts with the stated irradiation protocol

    Minor

    The results report analyzing irradiated cells four days after treatment, while the cell-culture methods specify analysis at 7, 10, or 15 days. The methods do not account for the reported four-day measurement.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., Hoeijmakers, J. H. J., de Bruin, A., Hara, E., & Campisi, J.
Affiliations
  • Buck Institute for Research on Aging (US)
  • Japanese Foundation For Cancer Research (JP)
  • Utrecht University (NL)
  • Erasmus MC (NL)
  • Albert Einstein College of Medicine (US)
  • National Institute for Public Health and the Environment (NL)
Corresponding author
Campisi, Judith
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2014-12
Volume
31
Issue
6
Pages
722-733
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2014.11.012
PMC
PMC4349629
OpenAlex
W1977362098
Cited by
2,045
References
48
Citations by year
2026: 209 · 2025: 211 · 2024: 228 · 2023: 229 · 2022: 204 · 2021: 234 · 2020: 213 · 2019: 162 · 2018: 138 · 2017: 100 · 2016: 78 · 2015: 36 · 2014: 1 · 2013: 1
FWCI
69.36
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • Rivm (National Institute for Public Health and the Environment) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
  • American Italian Cancer Foundation
  • Japan Science and Technology Agency
  • U.S. NIH (AG017242, AG009909, AG041122, CA166347)
  • European Council Advanced Grant (GA233424)
Topics
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
cellular senescence, senescence-associated secretory phenotype, wound healing, PDGF-AA, myofibroblast differentiation, senescent fibroblasts, tissue repair, senescent cell elimination
MeSH terms
Animals, Cell Differentiation, Female, Fibroblasts, Male, Mesoderm, Mice, Transgenic, Platelet-Derived Growth Factor, Wound Healing, Cellular Senescence, Apoptosis, Transgenes, Endothelial Cells, Luminescence, Mice, Myofibroblasts

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review