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.

How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models

“…This peculiar feature elegantly illustrates how chemotherapy damages the feather follicle: in the perturbed feathers, only the branched area showed reduced cell proliferation with concomitant reduction of Shh expression. The rachis region remained unperturbed (Figure G) . These results pinpoint a specific role of Shh signalling in chemotherapy‐induced tissue damage, which is further confirmed in the CIA mouse model .…”

“…These experimentally well‐supported, conventional concepts of CIA pathobiology became greatly enriched when the response of chicken feather follicles to chemotherapy was examined. This approach revealed that, unexpectedly, Shh signalling is also prominently involved in the follicular damage response . Although it is incompletely understood how specifically Shh signalling is involved, and what are the upstream events that inhibit Shh gene expression, the implication of this additional, important pathway represents a major step‐forward in CIA pathobiology, not the least since it invites novel CIA intervention strategies that had previously not been considered.…”

Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy

“…We found that WNT and hedgehog pathways fit this trend (Supplementary Table S3). Hedgehog signaling has been shown to be downregulated by cyclophosphamide in growing HFs (35). …”

Early Dengue Virus Infection in Human Skin: A Cycle of Inflammation and Infectivity

“…A recent unique study addressed a cancer-related clinical issue by perturbing feather growth with chemotherapeutic agents (Xie et al, 2015). Cyclophosphamide (CYP) has been shown to cause chemotherapyinduced alopecia (CIA) in mice and humans.…”