Fibroblasts cultured from venous ulcers display cellular characteristics of senescence

Mendez, Martha; Stanley, Andrew; Park, Heeyoung; Shon, Karen; Phillips, Tania J.; Menzoı́an, James O.

doi:10.1016/s0741-5214(98)70064-3

Cited by 189 publications

(141 citation statements)

References 25 publications

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“…The identification of iron accumulation in macrophages as the prime event in the complex pathogenesis of CVUs eventually driving persistent inflammation and tissue damage is also of major relevance for other chronic inflammatory disorders with enhanced iron storage in macrophages, like arteriosclerosis, multiple sclerosis, and other neurodegenerative diseases (79)(80)(81)(82). Taken together, our findings provide powerful insight into the role of an iron-induced macrophage population in vivo.…”

Section: Figurementioning

confidence: 58%

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

Sindrilaru¹,

Peters²,

Wieschalka³

et al. 2011

J. Clin. Invest.

951

790

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Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages -as was found to occur in human chronic venous leg ulcers and the mouse model -induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16 INK4a -dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.

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Section: Figurementioning

confidence: 58%

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

Sindrilaru¹,

Peters²,

Wieschalka³

et al. 2011

J. Clin. Invest.

951

790

View full text Add to dashboard Cite

show abstract

“…Alterations in the locally resident fibroblast populations and/or their proliferative capacities have a major impact on wound healing responses and are likely to play a significant role in age-related wound healing deficiencies (Campisi et al, 1998;Mendez et al, 1998). We show that TG2 is a key factor controlling fibroblast activities relevant to the wound healing response, including migration, generation of tension in the ECM and regulation of MMP activity.…”

Section: Function Of Tg2 In Wound Healingmentioning

confidence: 79%

Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses

Stephens

Grenard

Aeschlimann

et al. 2004

Journal of Cell Science

136

130

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Tissue transglutaminase (TG2) affects cell-matrix interactions in cell spreading, migration and extracellular matrix (ECM) reorganisation. Using fibroblasts deficient in TG2 or overexpressing normal or crosslinking-deficient enzyme, we show that the extracellular crosslinking activity and intracellular G-protein function in signal transduction contribute differentially to regulation of cell-matrix interactions. TG2-deficient cells displayed normal attachment but delayed spreading on ECM substrata and defects in motility unrelated to crosslinking. Blocking antibodies to TG2 failed to induce similar defects in normal fibroblasts. TG2-deficient fibroblasts had defects in focal adhesion turnover and stress fibre formation, showed changes in focal adhesion kinase (FAK) phosphorylation and failed to activate protein kinase C α (PKCα). Phospholipase C (PLC) and PKCα inhibitors blocked spreading of normal fibroblasts whilst PKC activators induced spreading in TG2-deficient cells. In contrast, ECM remodelling was not only compromised by TG2 deficiency but also by overexpression of dominant negative enzyme and TG inhibitors. TG2 activity increased matrix tension and was required for membrane type 1-MMP (MT1-MMP)-dependent activation of MMP-2. Our results demonstrate that TG2 is involved in the control of dynamic adhesion formation in cell spreading and migration via regulation of phospholipase C activity. By virtue of its crosslinking activity, the enzyme plays a central role in regulating ECM remodelling.

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“…Of particular interest, cultured fibroblasts from chronic skin ulcers showed characteristics of replicative senescence cells, implying a state of quiescence (11,14). In addition, premature fibroblast senescence may contribute to delay of the wound healing process in venous leg ulcers and has been associated with poor prognosis (15,16). Thus, in order to achieve completion of the wound healing process, some growth factors must be released from platelets or injected into wound areas at certain threshold concentrations.…”

Section: Discussionmentioning

confidence: 99%

Platelet-rich plasma induces increased expression of G1 cell cycle regulators, type I collagen, and matrix metalloproteinase-1 in human skin fibroblasts

Cho

Kim²,

Lee

2011

Int J Mol Med

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Abstract. Platelet-rich plasma (PRP) is derived from fresh whole blood, which contains a high concentration of platelets. Recently, PRP has been used for skin wound healing and rejuvenation. However, the molecular mechanisms underlying PRP-inducing wound healing processes are still largely unknown. The aim of this study is to evaluate the effect of PRP on the expression of G1 cell cycle regulatory proteins, type I collagen, matrix metalloproteinase-1 (MMP-1), and MMP-2 in human skin fibroblasts (HSF). We performed a cell proliferation and a migration assay, immunoblotting, and a chloramphenicol acetyltransferase (CAT) assay in PRP-treated human skin fibroblasts. PRP treatment induced increased rates of cell proliferation and cell migration. Expression of cyclin A protein was increased by a low concentration (0.5%) of PRP-treated HSF. In addition, expression of Rb, cyclin E, and cyclin-dependent kinase 4 proteins was increased by a high concentration (5%) of PRP-treated HSF. High concentration of PRP induced an up-regulation of type I collagen, MMP-1, and MMP-2 expression in HSF. Taken together, PRP treatment induced an increase in expression of G1 cell cycle regulators, type I collagen and MMP-1, thereby accelerating the wound healing process.

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Fibroblasts cultured from venous ulcers display cellular characteristics of senescence

Abstract: Fibroblasts cultured from venous ulcers exhibited characteristics associated with senescent cells. Accumulation of senescent cell in ulcer environment may be associated with impaired healing.

Cited by 189 publications

References 25 publications

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses

Platelet-rich plasma induces increased expression of G1 cell cycle regulators, type I collagen, and matrix metalloproteinase-1 in human skin fibroblasts

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