The Matricellular Protein CCN1/CYR61 Induces Fibroblast Senescence and Restricts Fibrosis in Cutaneous Wound Healing

By Joon-Il Jun, L. Lau. Nature Cell Biology, 2010

916 citations recorded by the source corpus.

Cellular senescence is a recognized mechanism of tumour suppression; however, its contribution to other pathologies is not well understood. We show that the matricellular protein CCN1 (also known as CYR61; cysteine-rich protein 61), which is dynamically expressed at sites of wound repair, can induce fibroblast senescence by binding to integrin α6β1 and the heparan sulphate proteoglycans (receptors involved in cell adhesion). CCN1 induces DNA damage response pathways and activates p53 and the RAC1–NOX1 complex, which generates reactive oxygen species (ROS). This results in the ROS-dependent activation of the p16INK4a/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes. Senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes in wild-type mice. These processes are lost in knockin mice that express a senescence-defective Ccn1 mutant, resulting in exacerbated fibrosis. Topical application of CCN1 protein to wounds reverses these defects. Thus, fibroblast senescence is a CCN1-dependent wound healing response in cutaneous injury that functions to curb fibrosis during tissue repair.

Subfields: Dermatology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/021909655ca17d7829e0033f9477ac406f78e186

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Dermatology

1. Jesús Gil
2. P. Jat
3. J. Campisi
4. J. Kirkland
5. J. V. van Deursen
6. R. Kumari
7. Nicolás Herranz
8. T. Tchkonia

In Molecular Biology

1. J. Campisi
2. Jesús Gil
3. M. Demaria
4. Adam Freund
5. T. Tchkonia
6. J. Kirkland
7. F. Rodier
8. J. V. van Deursen

Citations in the corpus

• An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA. (2026, background): “In agreement with previous findings (Jun and Lau, 2010; Krizhanovsky et al., 2008), we also found that the presence of senescent cells restrains fibrosis.”
• p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phenotype (2011, background): “The MMPs have matrix-degrading and fibrolytic activity, which may limit fibrosis during wound healing (Krizhanovsky et al, 2008; Jun and Lau, 2010).”
• Senescence is a developmental mechanism that contributes to embryonic growth and patterning. (2013, background): “, 2005), fibrotic tissue (Jun and Lau, 2010; Krizhanovsky et al., 2008), and aging human skin (Dimri et al.”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “171), induce senescence in effector T cells, limiting their proliferation by the activation of the p38MAPK and p53 signaling pathways that control both the cell cycle inhibitors p16INK4a and p21WAF1 (355, 356).”
• Mechanisms and functions of cellular senescence. (2018, positive): “…response to a cutaneous wound and accelerate wound closure, in part thanks to secreting factors such as the extracellular matrix– associated signaling protein CCN1 and platelet-derived growth factor AA (PDGF-AA), reinforcing the idea that acute, nonpersis-tent senescence can be beneficial (8, 9).”
• Four faces of cellular senescence (2011, neutral): “Surprisingly, healing wounds accumulated senescent fibroblasts and myofibroblasts; this did not occur in mice in which wild-type CCN1 alleles were exchanged for mutant alleles encoding CCN1 proteins that cannot bind fibroblasts (Jun and Lau, 2010).”
• Lamin B1 loss is a senescence-associated biomarker (2012, background): “Finally, reactive oxygen species (ROS) are elevated in senescent cells, and ROS signaling is believed to mediate the senescence growth arrest (Lu and Finkel, 2008; Jun and Lau, 2010; Passos et al., 2010; Rai et al., 2011).”
• Aging, Cellular Senescence, and Cancer (2012, background): “In cutaneous wounds, senescent cells are presumably cleared upon resolution of the granulation tissue (149).”
• Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders (2011, neutral): “There were no overt side effects of senescent cell clearance in our model, even though it has been postulated that senescent cells enhance certain types of tissue repai”
• Senescence and apoptosis: dueling or complementary cell fates? (2014, neutral): “During the wound-healing response in skin, myofibroblasts proliferate and produce extracellular matrix [139].”