Mis-relocation of mesenchymal niche leads to permanent radiotherapy-induced alopecia from stem cell exhaustion due to failed new stem cell formation

Summary: Abstract Body: Permanent radiotherapy-induced alopecia (pRIA) is a type of scarring alopecia featured by loss of the entire hair follicle structure. Similar to most scarring alopecic diseases, how hair follicles (HFs) become absent in pRIA remains unknown and effective treatments are lacking. Using an animal model, we found that radiation induced premature entry into catagen (dystrophic catagen) with retraction of the growing HF epithelium, which was immediately followed by HF loss. Early in this dystrophic process, the dermal papilla fibroblast niche became disconnected from the receding HF epithelial strands due to protracted apoptosis and suppressed regenerative cell proliferation from prolonged p53 activation. In the absence of the mesenchymal niche, HFs failed to generate new epithelial HF stem cells (eHFSCs) and HFs became lost from stem cell exhaustion. We demonstrated that enhancing regenerative epithelial proliferation by boosting hedgehog signaling prevented HF loss by maintaining the dermal papilla-epithelial connection to support new HFSC formation. Our work highlights the essential role new HFSC formation during catagen in the maintenance of normal hair cycling. Preserving the mesenchymal niche to support new HFSC formation is a promising strategy to prevent pRIA and possibly other types of scarring alopecic diseases. Wei-Hung Wang¹, Yun-Shan Wu¹, Sung-Jan Lin¹ 1. Institute of Biomedical engineering, National Taiwan University, Taipei City, Taipei City, Taiwan. Stem Cell Biology, Tissue Regeneration and Wound Healing