STEMORE Co. Ltd, Incheon, South Korea.
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea.
Br J Dermatol. 2019 Sep;181(3):523-534. doi: 10.1111/bjd.17706. Epub 2019 Apr 21.
Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis. Therefore, tremendous efforts have been made to promote DPC hair inductivity.
The aim of this study was to investigate the mitogenic and hair inductive effects of hypoxia on DPCs and examine the underlying mechanism of hypoxia-induced stimulation of DPCs.
DPCs' hair inductivity was examined under normoxia (20% O ) and hypoxia (2% O ).
Hypoxia significantly increased the proliferation and delayed senescence of DPCs via Akt phosphorylation and downstream pathways. Hypoxia upregulated growth factor secretion of DPCs through the mitogen-activated protein kinase pathway. Hypoxia-preconditioned DPCs induced the telogen-to-anagen transition in C H mice, and also enhanced hair neogenesis in a hair reconstitution assay. Injected green fluorescent protein-labelled DPCs migrated to the outer root sheath of the hair follicle, and hypoxia-preconditioning increased survival and migration of DPCs in vivo. Conditioned medium obtained from hypoxia increased the hair length of mouse vibrissa follicles via upregulation of alkaline phosphatase, vascular endothelial growth factor, and glial cell line-derived neurotrophic factor. We examined the mechanism of this hypoxia-induced stimulation, and found that reactive oxygen species (ROS) play a key role. For example, inhibition of ROS generation by N-acetylcysteine or diphenyleneiodonium treatment attenuated DPCs' hypoxia-induced stimulation, but treatment with ROS donors induced mitogenic effects and anagen transition. NADPH oxidase 4 is highly expressed in the DPC nuclear region, and NOX4 knockout by CRISPR-Cas9 attenuated the hypoxia-induced stimulation of DPCs.
Our results suggest that DPC culture under hypoxia has great advantages over normoxia, and is a novel solution for producing DPCs for cell therapy. What's already known about this topic? Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis, but they are difficult to isolate and expand for use in cell therapy. Tremendous efforts have been made to increase proliferation of DPCs and promote their hair formation ability. What does this study add? Hypoxia (2% O ) culture of DPCs increases proliferation, delays senescence and enhances hair inductivity of DPCs. Reactive oxygen species play a key role in hypoxia-induced stimulation of DPC. What is the translational message? Preconditioning DPCs under hypoxia improves their hair regenerative potential, and is a novel solution for producing DPCs for cell therapy to treat hair loss.
真皮乳头细胞（DPC）在毛发再生和形态发生中起着关键作用。因此，人们已经做出了巨大的努力来促进 DPC 的毛发诱导能力。
本研究旨在探讨低氧对 DPC 的有丝分裂和毛发诱导作用，并研究低氧刺激 DPC 的潜在机制。
在常氧（20% O ）和低氧（2% O ）条件下检测 DPC 的毛发诱导能力。
低氧通过 Akt 磷酸化及其下游途径显著增加 DPC 的增殖并延缓衰老。低氧通过丝裂原活化蛋白激酶途径上调 DPC 生长因子的分泌。低氧预处理的 DPC 诱导 C H 小鼠从休止期向生长期转变，并在毛发重建实验中增强毛发新生。注射绿色荧光蛋白标记的 DPC 迁移到毛囊的外根鞘，低氧预处理增加了 DPC 在体内的存活和迁移。低氧条件培养基通过上调碱性磷酸酶、血管内皮生长因子和胶质细胞源性神经营养因子增加了小鼠触须毛囊的毛发生长。我们研究了这种低氧诱导刺激的机制，发现活性氧（ROS）起着关键作用。例如，N-乙酰半胱氨酸或二苯基碘鎓处理抑制 ROS 的产生可减弱 DPC 的低氧诱导刺激，但 ROS 供体的处理诱导有丝分裂作用和生长期转变。NADPH 氧化酶 4 在 DPC 核区高表达，CRISPR-Cas9 敲除 NOX4 减弱了 DPC 的低氧诱导刺激。
我们的结果表明，DPC 在低氧下培养比常氧更有优势，是用于细胞治疗的 DPC 生产的新方法。
真皮乳头细胞（DPC）在毛发再生和形态发生中起着关键作用，但它们难以分离和扩增用于细胞治疗。已经做出了巨大的努力来增加 DPC 的增殖并促进其毛发形成能力。
低氧（2% O ）培养 DPC 可增加增殖、延缓衰老并增强 DPC 的毛发诱导能力。活性氧在低氧诱导的 DPC 刺激中起着关键作用。
低氧预处理 DPC 可提高其毛发再生潜能，是用于细胞治疗以治疗脱发的 DPC 生产的新方法。
