Impaired stem cell functions, which gradually fail to replenish damaged and senescent cells in distinct organ parenchyma can lead to tissue atrophy and organ aging. This failure can either be due to an intrinsic dysfunction of stem/progenitor cells, the disruption of the corresponding stem cell niche, or a combination of both. Fibroblasts in the connective tissue region of many organs, such as skin, contribute to the formation of stem cell niche. Though the impact of the connective tissue resident fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unexplored. We here uncovered a novel redox sensitive role of transcription factor JunB, on the instalment of irreversible fibroblast senescence through the suppression of Insulin Growth Factor-1 (IGF-1) and the concomitant induction of the cell cycle inhibitor p16INK4A. Fibroblast senescence in turn profoundly disrupts the skin stem cells niche and its essential interactions with different stem cells thus enforcing depletion of stem cells pools and tissue decline. The skin aging phenotypes with atrophy of all skin layers, reduced skin resilience and tensile strength were partly restored when either p16INK4A was inactivated or IGF-1 was supplemented. However, these aging phenotypes and, importantly, the numbers of distinct stem cells were completely restored in the skin when JunB was silenced. We here show for the first time that JunB dependent IGF-1 suppression and p16INK4A upregulation in fibroblasts fundamentally enforce skin aging through the disruption of several stem cell niches. Our findings hold substantial promise for novel strategies to combat skin aging and associated pathologies.

ESDR334 - Pulling the Trigger on Tissue Decline and Rejuvenation in the connective tissue - A Novel Role for JunB

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING