Essential Roles for Early Growth Response Transcription Factor Egr-1 in Tissue Fibrosis and Wound Healing

Wu, Minghua; Melichian, Denisa S.; Garza, Mauricio De La; Gruner, Katherine; Bhattacharyya, Swati; Barr, Luke; Nair, Aisha; Shahrara, Shiva; Sporn, Peter H. S.; Mustoe, Thomas A.; Tourtellotte, Warren G.; Varga, John

doi:10.2353/ajpath.2009.090241

Cited by 99 publications

(104 citation statements)

References 54 publications

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“…Amplification of the molecular changes in our mouse model of Achilles tendon injury is consistent with the amplified phenotypes observed in experimentally induced models for fibrosis, atherosclerosis, cardiac hypertrophy, and liver regeneration in Egr1 -/-mutant mice (44,(46)(47)(48)(49)(50)(51).…”

Section: Figuresupporting

confidence: 60%

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

Guerquin¹,

Charvet²,

Nourissat³

et al. 2013

J. Clin. Invest.

212

253

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Tendon formation and repair rely on specific combinations of transcription factors, growth factors, and mechanical parameters that regulate the production and spatial organization of type I collagen. Here, we investigated the function of the zinc finger transcription factor EGR1 in tendon formation, healing, and repair using rodent animal models and mesenchymal stem cells (MSCs). Adult tendons of Egr1 -/-mice displayed a deficiency in the expression of tendon genes, including Scx, Col1a1, and Col1a2, and were mechanically weaker compared with their WT littermates. EGR1 was recruited to the Col1a1 and Col2a1 promoters in postnatal mouse tendons in vivo. Egr1 was required for the normal gene response following tendon injury in a mouse model of Achilles tendon healing. Forced Egr1 expression programmed MSCs toward the tendon lineage and promoted the formation of in vitro-engineered tendons from MSCs. The application of EGR1-producing MSCs increased the formation of tendon-like tissues in a rat model of Achilles tendon injury. We provide evidence that the ability of EGR1 to promote tendon differentiation is partially mediated by TGF-β2. This study demonstrates EGR1 involvement in adult tendon formation, healing, and repair and identifies Egr1 as a putative target in tendon repair strategies.

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Section: Figuresupporting

confidence: 60%

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

Guerquin¹,

Charvet²,

Nourissat³

et al. 2013

J. Clin. Invest.

212

253

View full text Add to dashboard Cite

show abstract

“…To date, no functional characterization of the injuryinduced expression of planarian egr genes has been reported. However, given the decrease reported here in the first mitotic peak after egr-4 RNAi and the demonstrated role of several egr genes in wound healing, tissue fibrosis and inflammatory responses in other models (Schmidt et al, 2008;Wu et al, 2009;Chen et al, 2006), it seems plausible that early egr genes expression in planarians is involved in the initial stages of regeneration.…”

Section: Egr-4 Rnai Disrupts Head Regeneration Without Impairing the mentioning

confidence: 80%

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians

et al. 2014

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During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/ β-catenin and Hh signaling pathways in re-establishing anteriorposterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/β-catenin pathway, together with expression analysis of brain-and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phasesan early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/β-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.

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“…In these reports, deficiency of Egr-1 attenuates fibrosis and fibrotic markers. 16,42 Tissue specific differences between the liver and these other organs in the contribution of Egr-1 to chemically-induced fibrosis may stem from the liver's predominant role in toxin metabolism. This is exemplified by the liver's unique capacity to regenerate after toxin-mediated hepatocyte loss, as well as after other forms of liver injury.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Fibrosis Is Enhanced and Accompanied by Robust Oval Cell Activation after Chronic Carbon Tetrachloride Administration to Egr-1-Deficient Mice

Pritchard

Nagy

2010

The American Journal of Pathology

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The transcription factor early growth response (Egr)؊1 regulates the expression of genes required for execution of the wound healing response. Multiple cycles of injury, coupled to incomplete wound healing, lead to fibrosis. Therefore, we hypothesized that Egr-1 is required for the development of hepatic fibrosis. To test this hypothesis, we exposed wildtype and egr-1 ؊/؊ mice to acute or chronic carbon tetrachloride (CCl 4 ). Acute CCl 4 exposure established a profibrotic milieu in the liver, including activation of hepatic stellate cells as well as expression of type 1 collagen genes and tissue inhibitor of matrix metalloproteinase 1 in both wild-type and egr-1 ؊/؊ mice. This response was exacerbated in egr-1 ؊/؊ mice. After chronic CCl 4 exposure, hepatic fibrosis was established in both genotypes; however, the fibrotic response was profoundly worsened in Egr-1-deficient mice. Importantly, enhanced fibrosis in egr-1 ؊/؊ mice was accompanied by a robust activation of the oval cell response, suggesting more severe liver injury and/or reduced hepatocyte proliferation when compared with wild-type mice. Hepatic expression of genes indicative of oval cell activation, as well as the number of cells expressing A6, a mouse oval cell marker, was greater in egr-1 ؊/؊ mice. Taken together, these data reveal novel roles for Egr-1 as a negative regulator of both CCl 4 -induced hepatic fibrosis and the oval cell response.

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Essential Roles for Early Growth Response Transcription Factor Egr-1 in Tissue Fibrosis and Wound Healing

Cited by 99 publications

References 54 publications

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians

Hepatic Fibrosis Is Enhanced and Accompanied by Robust Oval Cell Activation after Chronic Carbon Tetrachloride Administration to Egr-1-Deficient Mice

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