Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging

• Published in: Cell reports (Cambridge) 2021-08, Vol.36 (9), p.109634, Article 109634
• Main Authors: Maity, Pallab, Singh, Karmveer, Krug, Linda, Koroma, Albert, Hainzl, Adelheid, Bloch, Wilhelm, Kochanek, Stefan, Wlaschek, Meinhard, Schorpp-Kistner, Marina, Angel, Peter, Ignatius, Anita, Geiger, Hartmut, Scharffetter-Kochanek, Karin
• Format: Article
• Language: English
• Subjects: aging; Animals; Cell Communication; Cells, Cultured; Cellular Senescence; Collagen Type I - genetics; Collagen Type I - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; fibroblasts; Fibroblasts - metabolism; IGF-1; Insulin-Like Growth Factor I - metabolism; JunB; Mice; Mice, Knockout; p16INK4A; redox imbalance; skin; Skin - metabolism; Skin - pathology; Skin Aging; Stem Cell Niche; Stem Cells - metabolism; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxides - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109634

Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner—by reinstatement of IGF-1 and p16 levels—restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies. [Display omitted] •Mitochondrial redox imbalance (O2− accumulation) induces JunB in skin fibroblasts•JunB causes fibroblast senescence through p16 upregulation and IGF-1 downregulation•Fibroblast senescence disrupts metabolic and structural niches of skin stem cells•Disruption of stem cell niches depletes stem cells pools and causes skin atrophy Maity et al. demonstrate that JunB, a member of AP1 transcription factor family, is induced during mitochondrial redox imbalance in skin fibroblasts. JunB, through p16 upregulation and IGF-1 downregulation, causes fibroblasts senescence, which disrupts the skin stem cell niche and enforces depletion of stem cells pools and skin tissue decline.