title: Efficient keratinocyte differentiation strictly depends on JNK-induced soluble factors in fibroblasts.
abstract: Previous studies demonstrated that fibroblast-derived and JUN-dependent soluble factors have a crucial role on keratinocyte proliferation and differentiation during cutaneous wound healing. Furthermore, mice with a deficiency in Jun N-terminal kinases (JNKs) , JNK1 or JNK2, showed impaired skin development and delayed wound closure. To decipher the role of dermal JNK in keratinocyte behavior during these processes, we used a heterologous coculture model combining primary human keratinocytes and murine fibroblasts. Although cocultured JNK1/JNK2-deficient fibroblasts did not affect keratinocyte proliferation, temporal monitoring of the transcriptome of differentiating keratinocytes revealed that efficient keratinocyte differentiation not only requires the support by fibroblast-derived soluble factors, but is also critically dependent on JNK1 and JNK2 signaling in these cells. Moreover, we showed that the repertoire of fibroblast transcripts encoding secreted proteins is severely disarranged upon loss of JNK under the coculture conditions applied. Finally, our data demonstrate that efficient keratinocyte terminal differentiation requires constant presence of JNK-dependent and fibroblast-derived soluble factors. Taken together, our results imply that mesenchymal JNK has a pivotal role in the paracrine cross talk between dermal fibroblasts and epidermal keratinocytes during wound healing.
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Marion
authors: M
authors: Schumacher
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Christian
authors: C
authors: Schuster
authors: Division of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Zbigniew M
authors: ZM
authors: Rogon
authors: Division of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Tobias
authors: T
authors: Bauer
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Nevisa
authors: N
authors: Caushaj
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Sebastian
authors: S
authors: Baars
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Sibylle
authors: S
authors: Szabowski
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Christine
authors: C
authors: Bauer
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Marina
authors: M
authors: Schorpp-Kistner
authors: Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Germany; Junior Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors: Jochen
authors: J
authors: Hess
authors: Division of Pediatric Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Stefan
authors: S
authors: Holland-Cunz
authors: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Erwin F
authors: EF
authors: Wagner
authors: Division of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Roland
authors: R
authors: Eils
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany. Electronic address: p.angel@dkfz.de.
authors: Peter
authors: P
authors: Angel
authors: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Bettina
authors: B
authors: Hartenstein
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D014945:Wound Healing / Q000502:physiology
chemical_list: D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8