Lipid aldehydes from senescent cells reshape the ECM and propagate senescence

Summary: Abstract Body: Senescent dermal fibroblasts display reactive lipids which are part of the senescence-associated secretory phenotype (SASP). These lipids, such as 4-Hydroxynonenal (HNE) and oxidized phospholipids (OxPAPC), bind covalently to proteins. We investigated lipid-induced collagen modifications and their effects on skin cells, to assess consequences of senescent cells to the microenvironment. Using mass spectrometry and biochemical methods, we identified adducts of SASP lipids to collagen type I, II and IV and cultured skin cells on modified matrices or in skin equivalents containing modified matrices. In fibroblasts, HNE-modified collagen induced redox stress responses (HO1 and HSPA1A), while OxPAPC-modified collagen triggered inflammation. Both modifications increased MMP1 and MMP3 and reduced collagen I and III expression. Fibroblasts on HNE-collagen exhibited reduced proliferation determined by Ki67 expression. Both HNE and OxPAPC modified collagen led to elevated levels of reactive oxygen species (ROS) and further lipid peroxidation. In macrophages cultured on modified collagen the cytokine profiles suggested a modification dependent low grade inflammatory phenotype while Toll-like receptor (TLR4) signaling of the macrophages was impaired. In keratinocytes exposed to lipid-modified basal lamina collagen IV we observed transient stress and inflammatory responses suppressed MMP3/MMP9 expression. In organotypic skin equivalents produced with SASP-modified matrix we observed increased markers of cellular senescence (lower LaminB1, higher H2AX and p16 levels) and disturbed differentiation and parakeratosis induced by OxPAPC modification. We propose that senescent cells cause a long therm modification of the ECM through aldeydic SASP lipids and the modified matrix propagates a senescent phenotype. Sarah Jelleschitz^{1, 2}, Christopher Kremslehner^{1, 2}, Ionela-Mariana Nagelreiter^{1, 2}, Michaela Schirato^{1, 2}, Adrian Sandgren-Fors^{1, 2}, Maria Fedorova³, Zhixu Ni³, Gaelle Gendronneau⁴, Agnes Tessier⁴, Francesca Marcato⁴, Florian Gruber^{1, 2} 1. Dermatology, Medizinische Universitat Wien, Vienna, Vienna, Austria. 2. Christian Doppler Laboratory SKINMAGINE, Vienna, Austria. 3. Technische Universitat Dresden, Dresden, SN, Germany. 4. Perfums&Beaute, CHANEL, Pantin, France. Cell Communication Networks and Stromal Biology