title: Testing chemotherapeutic agents in the feather follicle identifies a selective blockade of cell proliferation and a key role for sonic hedgehog signaling in chemotherapy-induced tissue damage.
abstract: Chemotherapeutic agents induce complex tissue responses in vivo and damage normal organ functions. Here we use the feather follicle to investigate details of this damage response. We show that cyclophosphamide treatment, which causes chemotherapy-induced alopecia in mice and man, induces distinct defects in feather formation: feather branching is transiently and reversibly disrupted, thus leaving a morphological record of the impact of chemotherapeutic agents, whereas the rachis (feather axis) remains unperturbed. Similar defects are observed in feathers treated with 5-fluorouracil or taxol but not with doxorubicin or arabinofuranosyl cytidine (Ara-C). Selective blockade of cell proliferation was seen in the feather branching area, along with a downregulation of sonic hedgehog (Shh) transcription, but not in the equally proliferative rachis. Local delivery of the Shh inhibitor, cyclopamine, or Shh silencing both recapitulated this effect. In mouse hair follicles, those chemotherapeutic agents that disrupted feather formation also downregulated Shh gene expression and induced hair loss, whereas doxorubicin or Ara-C did not. Our results reveal a mechanism through which chemotherapeutic agents damage rapidly proliferating epithelial tissue, namely via the cell population-specific, Shh-dependent inhibition of proliferation. This mechanism may be targeted by future strategies to manage chemotherapy-induced tissue damage.
authors.affiliation: Institute of Life Sciences, Fuzhou University, Fuzhou, China.
authors.forename: Guojiang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Institute of Life Sciences, Fuzhou University, Fuzhou, China.
authors.forename: Hangwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Life Sciences, Fuzhou University, Fuzhou, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Institute of Life Sciences, Fuzhou University, Fuzhou, China.
authors.forename: Linyan
authors.initials: L
authors.lastname: Cai
authors.affiliation: Institute of Life Sciences, Fuzhou University, Fuzhou, China.
authors.forename: Guixuan
authors.initials: G
authors.lastname: Zhou
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Wanzhong
authors.initials: W
authors.lastname: He
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester, UK,; Department of Dermatology, University of Muenster, Muenster, Germany. Electronic address: raw600@gmail.com.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Institute of Life Sciences, Fuzhou University, Fuzhou, China.
authors.forename: Zhicao
authors.initials: Z
authors.lastname: Yue
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002645:Chickens; D015536:Down-Regulation / Q000187:drug effects; D005241:Feathers / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018859:Hair Follicle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins