Taxane chemotherapy induces premature aging and epigenetic changes in human hair follicles

Summary: Abstract Body: Taxane chemotherapy damages human scalp hair follicles (HFs) and their epithelial stem cells (eHFSCs) on multiple levels (e.g., excessive apoptosis, mitotic disruption, DNA damage, pathological EMT induction). Yet it is unclear if taxanes also promote premature HF aging. To explore this, we treated organ-cultured human anagen scalp HFs from 4 donors with paclitaxel (PTX, 100nM, 6 days). Quantitative immuno-histomorphometry revealed that PTX significantly decreased the protein expression of nuclear Lamin B1 in the peripheral rim and SIRT1 and PGC1α within the hair matrix epithelium, indicating premature HF aging/senescence. PTX also reduced the number of gp100+ cells in the hair matrix, thus facilitating premature greying. In the bulge, the number of K15+ eHFSCs and expression of collagen XVIIa1 were significantly reduced in PTX-treated HFs. Given that aging is also associated with epigenetic alterations, we next evaluated the global methylation patterns of PTX-treated HFs. This showed decreased levels of DNA methylation markers (5-methylcytosine, DNA-Methyltransferase 1) in eHFSCs, and elevated 5-hydroxymethylcytosine expression in hair matrix keratinocytes, documenting enhanced global DNA demethylation. Thus, taxanes trigger premature HF aging, also at the level of epigenetic changes, both in maximally proliferating hair matrix keratinocytes and in quiescent eHFSCs, thereby reducing the HF’s regenerative capacity and facilitating the development of permanent alopecia. The taxane-induced global DNA hypomethylation favors the expression of normally silenced genes, which may include aging-promoting ones. We are currently exploring in scalp skin organ culture if topical treatment with melatonin protects against the taxane-induced HF damage reported above. Kinga Linowiecka^{1, 2, 3}, Aysun Akhundlu³, Yeqin Dai³, Francesca Dostillio³, Alan Bauman⁴, Ramtin Kassir⁵, Ralf Paus^{2, 3}, Jérémy Chéret^{2, 3} 1. Department of Human Biology, Nicolaus Copernicus University in Torun, Torun, Poland. 2. Cutaneon - Skin & Hair Innovations GmbH, Hamburg & Berlin, Germany. 3. Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, United States. 4. Bauman Medical Group, Boca Raton, FL, United States. 5. Kassir Plastic Surgery, New York, NY, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing