title: Alteration of skin wound healing in keratinocyte-specific mediator complex subunit 1 null mice.
abstract: MED1 (Mediator complex subunit 1) is a co-activator of various transcription factors that function in multiple transcriptional pathways. We have already established keratinocyte-specific MED1 null mice (Med1(epi-/-)) that develop epidermal hyperplasia. Herein, to investigate the function(s) of MED1 in skin wound healing, full-thickness skin wounds were generated in Med1(epi-/-) and age-matched wild-type mice and the healing process was analyzed. Macroscopic wound closure and the re-epithelialization rate were accelerated in 8-week-old Med1(epi-/-) mice compared with age-matched wild-type mice. Increased lengths of migrating epithelial tongues and numbers of Ki67-positive cells at the wounded epidermis were observed in 8-week-old Med1(epi-/-) mice, whereas wound contraction and the area of α-SMA-positive myofibroblasts in the granulation tissue were unaffected. Migration was enhanced in Med1(epi-/-) keratinocytes compared with wild-type keratinocytes in vitro. Immunoblotting revealed that the expression of follistatin was significantly decreased in Med1(epi-/-) keratinocytes. Moreover, the mitogen-activated protein kinase pathway was enhanced before and after treatment of Med1(epi-/-) keratinocytes with activin A in vitro. Cell-cycle analysis showed an increased ratio of S phase cells after activin A treatment of Med1(epi-/-) keratinocytes compared with wild-type keratinocytes. These findings indicate that the activin-follistatin system is involved in this acceleration of skin wound healing in 8-week-old Med1(epi-/-) mice. On the other hand, skin wound healing in 6-month-old Med1(epi-/-) mice was significantly delayed with decreased numbers of Ki67-positive cells at the wounded epidermis as well as BrdU-positive label retaining cells in hair follicles compared with age-matched wild-type mice. These results agree with our previous observation that hair follicle bulge stem cells are reduced in older Med1(epi-/-) mice, indicating a decreased contribution of hair follicle stem cells to epidermal regeneration after wounding in 6-month-old Med1(epi-/-) mice. This study sheds light on the novel function of MED1 in keratinocytes and suggests a possible new therapeutic approach for skin wound healing and aging.
authors.affiliation: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Noguchi
authors.affiliation: Department of Dermatology, Osaka General Medical Center, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Inui
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
authors.affiliation: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
mesh_terms: D000199:Actins / Q000378:metabolism; D028341:Activins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D038681:Follistatin / Q000378:metabolism; D018859:Hair Follicle / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D062326:Re-Epithelialization / Q000502:physiology; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000199:Actins; D038681:Follistatin; D019394:Ki-67 Antigen; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; C544013:alpha-smooth muscle actin, mouse; D028341:Activins; D020928:Mitogen-Activated Protein Kinases