Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy.
Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy.
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DOI：
10.1158/0008-5472.can-17-0667
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发表时间：
2017-11-15
期刊：
影响因子：
11.2
通讯作者：
Lin SJ
中科院分区：
文献类型：
--
作者：
Huang WY;Lai SF;Chiu HY;Chang M;Plikus MV;Chan CC;Chen YT;Tsao PN;Yang TL;Lee HS;Chi P;Lin SJ
化疗和放疗引起的遗传毒性脱发在癌症治疗中经常遇到，并且缺乏有效的治疗方法。在生长的毛囊（HF）中，静止干细胞（SC）维持在凸起区域，基部的毛球含有快速分裂但对遗传毒性敏感的过渡扩增细胞（TAC），维持毛发生长。遗传毒性诱导的HF损伤如何修复仍不清楚。我们在这里报告，HF动员异位祖细胞从不同的TAC车厢再生适应电离辐射（IR）诱导的营养不良的严重程度。具体而言，低剂量IR后，角蛋白5+基底毛球祖细胞，而不是凸起SC，被迅速激活，以补充基质细胞和再生的HF的所有同心层，证明其可塑性。在高剂量IR后，当基质和毛球细胞都耗尽时，存活的外根鞘细胞迅速获得SC样状态并促进HF再生。然后，它们的后代回到SC生态位，并支持HF生长的新周期。我们还发现，IR诱导HF营养不良和脱发，并抑制WNT信号转导的p53和剂量依赖性的方式。增强WNT信号转导减弱了p53的抑制作用，增强了遗传毒性损伤后的异位祖细胞增殖，从而预防IR和环磷酰胺诱导的脱发。因此，靶向激活TAC衍生的祖细胞，而不是静止的隆起SC，用于生长期HF修复可能是预防化疗和放疗引起的脱发的潜在方法。
Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HF mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin5+ basal hair bulb progenitors, rather than bulge SC, were quickly activated to replenish matrix cells and regenerated all concentric layers of HF, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired a SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SC, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy.