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在羽毛囊内测试化疗药物,鉴定出对细胞增殖的选择性阻断,以及 sonic hedgehog 信号在化疗引起的组织损伤中的关键作用。

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.

机构信息

Institute of Life Sciences, Fuzhou University, Fuzhou, China.

National Institute of Biological Sciences, Beijing, China.

出版信息

J Invest Dermatol. 2015 Mar;135(3):690-700. doi: 10.1038/jid.2014.409. Epub 2014 Sep 18.

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.

摘要

化疗药物在体内诱导复杂的组织反应,并损害正常器官功能。在这里,我们利用羽毛囊研究这种损伤反应的细节。我们发现,环磷酰胺治疗会导致小鼠和人类的化疗性脱发,从而导致羽毛形成的明显缺陷:羽毛分支暂时且可逆地受到干扰,从而留下化疗药物影响的形态记录,而羽轴(羽毛轴)则不受干扰。用 5-氟尿嘧啶或紫杉醇处理的羽毛也观察到类似的缺陷,但用阿霉素或阿拉伯呋喃糖基胞嘧啶(Ara-C)处理则没有。在羽毛分支区域观察到选择性的细胞增殖阻断,同时 sonic hedgehog(Shh)转录下调,但在同样增殖的羽轴则没有。局部给予 Shh 抑制剂环巴胺或 Shh 沉默均可重现这种效应。在小鼠毛囊中,那些破坏羽毛形成的化疗药物也下调 Shh 基因表达并诱导脱发,而阿霉素或 Ara-C 则没有。我们的结果揭示了化疗药物损伤快速增殖的上皮组织的一种机制,即通过细胞群体特异性、Shh 依赖性的增殖抑制。这种机制可能成为未来管理化疗引起的组织损伤的策略的靶点。

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