Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease.
Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease.
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DOI：
10.1182/blood-2017-06-792614
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发表时间：
2018-05
期刊：
影响因子：
20.3
通讯作者：
Shuichiro Takahashi;D. Hashimoto;Eiko Hayase;Reiki Ogasawara;H. Ohigashi;Takahide Ara;Emi Yokoyama;K. Ebata;S. Matsuoka;G. Hill;J. Sugita;M. Onozawa;T. Teshima
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文献类型：
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作者：
Shuichiro Takahashi;D. Hashimoto;Eiko Hayase;Reiki Ogasawara;H. Ohigashi;Takahide Ara;Emi Yokoyama;K. Ebata;S. Matsuoka;G. Hill;J. Sugita;M. Onozawa;T. Teshima
移植物抗宿主病（GVHD）是同种异体干细胞移植（SCT）后的主要并发症。新的证据表明 GVHD 会导致肠道干细胞损伤。然而，皮肤干细胞是否可以作为皮肤 GVHD 的靶点仍有待研究。 Lgr5+ 毛囊干细胞 (HFSC) 有助于毛囊发生，并具有再生所有修复中的上皮细胞的多能能力。我们研究了 SCT 后 Lgr5+ HFSC 的命运，并利用 SCT 小鼠模型探索了保护 Lgr5+ HFSC 免受 GVHD 侵害的新疗法。我们发现，GVHD 减少了 Lgr5+ HFSC，这与 SCT 后毛发再生和皮肤伤口愈合受损有关。外用皮质类固醇是治疗包括 GVHD 在内的多种皮肤疾病的标准疗法，尽管具有抗炎作用，但它会损害 HFSC，并且无法改善皮肤稳态。相比之下，JAK1/2 抑制剂鲁索替尼显着改善皮肤 GVHD，保护 Lgr5+ HFSC，并在 SCT 后恢复毛发再生和伤口愈合。我们首次发现 GVHD 以 Lgr5+ HFSC 为目标，而局部用鲁索替尼代表了一种在 GVHD 中保护皮肤干细胞和维持皮肤稳态的新策略。
Graft-versus-host disease (GVHD) is the major complication after allogeneic stem cell transplantation (SCT). Emerging evidence indicates that GVHD leads to injury of intestinal stem cells. However, it remains to be investigated whether skin stem cells could be targeted in skin GVHD. Lgr5+ hair follicle stem cells (HFSCs) contribute to folliculogenesis and have a multipotent capacity to regenerate all epithelial cells in repair. We studied the fate of Lgr5+ HFSCs after SCT and explored the novel treatment to protect Lgr5+ HFSCs against GVHD using murine models of SCT. We found that GVHD reduced Lgr5+ HFSCs in association with impaired hair regeneration and wound healing in the skin after SCT. Topical corticosteroids, a standard of care for a wide range of skin disorders including GVHD, damaged HFSCs and failed to improve skin homeostasis, despite of their anti-inflammatory effects. In contrast, JAK1/2 inhibitor ruxolitinib significantly ameliorated skin GVHD, protected Lgr5+ HFSCs, and restored hair regeneration and wound healing after SCT. We, for the first time, found that GVHD targets Lgr5+ HFSCs and that topical ruxolitinib represents a novel strategy to protect skin stem cells and maintain skin homeostasis in GVHD.