Role of pro-oxidative connective tissue in skin aging – Molecular mechanisms and therapeutic strategies

• Applicant: Professorin Dr. Karin Scharffetter-Kochanek
• Subject Area: Dermatology ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432048315

• Final Report Year: 2024

Final Report Abstract

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 instalment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforce 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 p16INK4A 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.

Publications

• Acquired Disorders of Collagen and Elastin. Braun-Falco´s Dermatology, 1-17. Springer Berlin Heidelberg.
  Scharffetter-Kochanek, Karin & Makrantonaki, Evgenia
  
• A Wnt5a-Cdc42 axis controls aging and rejuvenation of hair-follicle stem cells. Aging, 13(4), 4778-4793.
  Tiwari, Rajiv L.; Mishra, Pratibha; Martin, Nicola; George, Nikhil Oommen; Sakk, Vadim; Soller, Karin; Nalapareddy, Kodandaramireddy; Nattamai, Kalpana; Scharffetter-Kochanek, Karin; Florian, Maria Carolina & Geiger, Hartmut
  
• Connective Tissue and Fibroblast Senescence in Skin Aging. Journal of Investigative Dermatology, 141(4), 985-992.
  Wlaschek, Meinhard; Maity, Pallab; Makrantonaki, Evgenia & Scharffetter-Kochanek, Karin
  
• Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging. Cell Reports, 36(9), 109634.
  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