title: Transcription factor EGR1 directs tendon differentiation and promotes tendon repair.
abstract: 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.
authors.affiliation: UPMC, Univ Paris 06, Paris, France.
authors.forename: Marie-Justine
authors.initials: MJ
authors.lastname: Guerquin
authors.forename: Benjamin
authors.initials: B
authors.lastname: Charvet
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Nourissat
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Havis
authors.forename: Olivier
authors.initials: O
authors.lastname: Ronsin
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Bonnin
authors.forename: Mathilde
authors.initials: M
authors.lastname: Ruggiu
authors.forename: Isabel
authors.initials: I
authors.lastname: Olivera-Martinez
authors.forename: Nicolas
authors.initials: N
authors.lastname: Robert
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Lu
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.forename: Tristan
authors.initials: T
authors.lastname: Baumberger
authors.forename: Levon
authors.initials: L
authors.lastname: Doursounian
authors.forename: Francis
authors.initials: F
authors.lastname: Berenbaum
authors.forename: Delphine
authors.initials: D
authors.lastname: Duprez
mesh_terms: D000125:Achilles Tendon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002642:Chick Embryo; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D055119:Elastic Modulus; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration; D015398:Signal Transduction; D059467:Transcriptome; D053781:Transforming Growth Factor beta2 / Q000502:physiology; D014945:Wound Healing
chemical_list: C447413:Col2a1 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024043:Collagen Type II; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D053781:Transforming Growth Factor beta2