title: Master regulators in primary skin fibroblast fate reprogramming in a human ex vivo model of chronic wounds.
abstract: Fibroblasts are important players in regulating tissue homeostasis. In the dermis, they are involved in wound healing where they differentiate into contractile myofibroblasts leading to wound closure. In nonhealing chronic wounds, fibroblasts fail to undertake differentiation. We established and used a human ex vivo model of chronic wounds where fibroblasts can undergo normal myofibroblast differentiation, or take on a nondifferentiable pathological state. At the whole genome scale, we identified the genes that are differentially regulated in these two cell fates. By coupling the search of evolutionary conserved regulatory elements with global gene network expression changes, we identified transcription factors (TF) potentially involved in myofibroblast differentiation, and constructed a network of relationship between these key factors. Among these, we found that TCF4, SOX9, EGR2, and FOXS1 are major regulators of fibroblast to myofibroblast differentiation. Conversely, down-regulation of MEOX2, SIX2, and MAF causes reprogramming of fibroblasts to myofibroblasts even in absence of TGF-β, the natural inducer of myofibroblast differentiation. These results provide insight into the fibroblast differentiation program and reveal a TF network essential for cellular reprogramming. They could lead to the development of new therapeutics to treat fibroblast-related human pathologies.
authors.affiliation: Functional Imaging of Transcription, CNRS UMR8197, ENS, IBENS, Paris, France.
authors.forename: Maïté
authors.initials: M
authors.lastname: Noizet
authors.affiliation: Functional Imaging of Transcription, CNRS UMR8197, ENS, IBENS, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lagoutte
authors.affiliation: Dyogen Group, CNRS UMR8197, ENS, IBENS, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Gratigny
authors.affiliation: URGO Group, Chenôve, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Bouschbacher
authors.affiliation: Department of Vascular Medicine, Jean-Paul Belmondo Institute, Paris Saint Joseph Hospital, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lazareth
authors.affiliation: Dyogen Group, CNRS UMR8197, ENS, IBENS, Paris, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Roest Crollius
authors.affiliation: Functional Imaging of Transcription, CNRS UMR8197, ENS, IBENS, Paris, France.|Genetics, Genomics and Development, Molecular and Cell Biology, University of California, Berkeley, California.
authors.forename: Xavier
authors.initials: X
authors.lastname: Darzacq
authors.affiliation: Functional Imaging of Transcription, CNRS UMR8197, ENS, IBENS, Paris, France.|Genetics, Genomics and Development, Molecular and Cell Biology, University of California, Berkeley, California.|UFR SDV, University Paris Diderot, Paris Cite Sorbonne, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Dugast-Darzacq
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D000067470:Cellular Reprogramming Techniques; D015536:Down-Regulation; D005122:Exudates and Transudates / Q000166:cytology; D006801:Humans; D008875:Middle Aged; D058628:Myofibroblasts / Q000166:cytology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014647:Varicose Ulcer / Q000473:pathology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta