Amphiregulin promotes hair regeneration of skin-derived precursors via the PI3K and MAPK pathways.
Amphiregulin promotes hair regeneration of skin-derived precursors via the PI3K and MAPK pathways.
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双调蛋白通过 PI3K 和 MAPK 途径促进皮肤源性前体的毛发再生
DOI：
10.1111/cpr.13106
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发表时间：
2021-09
影响因子：
8.5
通讯作者：
Chu W
中科院分区：
文献类型：
--
作者：
Lu Q;Gao Y;Fan Z;Xiao X;Chen Y;Si Y;Kong D;Wang S;Liao M;Chen X;Wang X;Chu W
脱发治疗存在重大的临床挑战，包括相关药物的疗效差和用于移植的毛囊（HF）不足。皮肤来源的前体（SKPs）作为基于干细胞的毛发再生疗法表现出巨大的潜力;然而，SKPs的增殖和毛发诱导能力在培养过程中逐渐降低。我们描述了一个3D共培养系统，伴随着基因和基因组的京都百科全书和基因本体富集分析，以确定增强SKP干性的关键因素和途径，并使用碱性磷酸酶测定，Ki-67染色，HF重建，Western印迹和免疫荧光染色进行验证。利用相应的重组蛋白或小干扰RNA沉默在体外证实了上调的基因，以及在体内评价了休止期向生长期的转变和HF重建。3D共培养系统显示，表皮干细胞和脂肪来源的干细胞通过双调蛋白（AREG）增强了SKP增殖和HF再生能力，促进的干细胞性使SKP获得更早的休止期至生长期过渡和高效的HF重建。相比之下，AREG信号传导下游的磷酸肌醇3-激酶（PI 3 K）和丝裂原活化蛋白激酶（MAPK）途径的抑制剂导致完全相反的活性。通过利用3D共培养模型，我们确定AREG通过PI 3 K和MAPK途径增强增殖和毛发诱导能力来促进SKP的干性。这些发现表明AREG疗法作为治疗脱发的潜在有前途的方法。3D共培养系统揭示了Epi‐ SC和ASC帮助SKPs表达更高水平的AREG，导致下游PI 3 K和MAPK通路的上调。结果，促进了SKP的增殖和HF再生能力。
There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; however, the proliferation and hair‐inducing capacity of SKPs gradually decrease during culturing. We describe a 3D co‐culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki‐67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small‐interfering RNA silencing in vitro, as well as the evaluation of telogen‐to‐anagen transition and HF reconstitution in vivo. The 3D co‐culture system revealed that epidermal stem cells and adipose‐derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen‐to‐anagen transition and high‐efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities. By exploiting a 3D co‐culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair‐inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia. The 3D co‐culture system reveals that Epi‐SCs and ASCs help SKPs express a higher level of AREG, leading to upregulation of the downstream PI3K and MAPK pathways. As a result, SKP capabilities of proliferation and HF regeneration are promoted.
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