黑素干细胞及其在白癜风复色过程中的作用研究进展
Progress in the Study of Melanocyte Stem Cells and Their Role in the Repigmentation Process of Vitiligo
DOI: 10.12677/pi.2024.133027, PDF, HTML, XML, 下载: 63  浏览: 96 
作者: 于 梦, 岳芸芸*:中国药科大学中药学院,江苏 南京;尚 靖*:中国药科大学中药学院,江苏 南京;中国药科大学江苏省中药评价与转化重点实验室,江苏 南京;中国药科大学天然药物活性组分与药效国家重点实验室,江苏 南京;国家药品监督管理局化妆品研究与评价重点实验室,北京
关键词: 黑素干细胞再生信号调控白癜风Melanocyte Stem Cell Regeneration Signaling Regulation Vitiligo
摘要: 黑素干细胞具有无限自我更新能力,在一定条件(如伤口愈合、基因毒性药物处理和紫外线照射等)的刺激下,细胞或组织会通过再生来修复受损,即招募干细胞来分化为成熟的黑素细胞。近年来有研究发现黑素干细胞可作为皮肤和毛发的黑素细胞库,这为许多色素紊乱性疾病的治疗带来了新的希望。本文主要对黑素干细胞进行了介绍,并对黑素干细胞再生的关键信号通路、与邻近细胞之间的串扰及其在白癜风复色过程中的作用进行讨论。
Abstract: Melanocyte stem cells have an unlimited self-renewal capacity, and under the stimulation of certain conditions (e.g. wound healing, genotoxic drug treatment, and ultraviolet irradiation, etc.), the cells or tissues will repair the damage by regeneration, i.e., recruiting stem cells to differentiate into mature melanocytes. In recent years, it has been found that melanocyte stem cells can serve as a reservoir of melanocytes for the skin and hair, which brings new hope for the treatment of many pigmentation disorders. This paper focuses on melanocyte stem cells and discusses the key signaling pathways of regeneration, crosstalk with neighboring cells and their role in vitiligo repigmentation.
文章引用:于梦, 岳芸芸, 尚靖. 黑素干细胞及其在白癜风复色过程中的作用研究进展[J]. 药物资讯, 2024, 13(3): 223-231. https://doi.org/10.12677/pi.2024.133027

1. 引言

干细胞(SCs)被定义为具有在分化后产生成熟细胞和通过自我更新来维持自身的双重能力的细胞。在不同的生理和病理条件下,它们可以用来维持组织稳态,如发育、损伤和疾病等 [1] 。黑素干细胞是一种细胞谱系特异性成体干细胞,位于毛囊的隆突区–次级毛芽处 [2] 。在生理状态下,黑素干细胞通常处于未成熟和休眠状态,只有在毛囊生长期早期被激活,为皮肤和毛发提供黑色素 [3] 。在病理状态下,黑素干细胞仍然存在于色素脱失性疾病白癜风的皮损区中,并提供了用于复色的黑素细胞 [4] 。因此,深入研究调控黑素干细胞的分子机制及其在白癜风治疗中的作用对于理解色素相关疾病具有重要意义。

2. 黑素干细胞概述

2.1. 黑素干细胞的来源和生物学特征

黑素干细胞发育过程相对复杂。哺乳动物中,黑素细胞来源于胚胎发育时期的神经嵴(Neural crest) [5] 。在鼠胚胎发育的第10.5天(embryonic day 10.5, E10.5),神经嵴细胞分化为性别决定区域SOX10阳性的神经嵴细胞,后者进一步分化为能表达配对盒基因(PAX3)、小眼畸形相关转录因子(MITF)、多巴色素异构酶(DCT)和酪氨酸蛋白激酶(KIT)基因的黑素前体细胞 [6] 。此时黑素前体细胞从神经管向皮肤的真皮层迁移。随后,在E13.5,它们进入表皮,主动迁移并向腹侧中线增殖。E14.5时毛囊形态开始发生,黑素前体细胞进入新生成的毛囊。在从E17.5到刚出生(Postnatal day 0, P0)的毛囊中,黑素前体细胞被分离成两个群体:一个群体定位于毛囊毛球中,在那里它们分化为成熟的黑素细胞,并在第一个毛发周期为毛发提供黑色素;另一个群体定居在毛囊隆突区,分化为黑素干细胞,作为储存库为再生的成年毛囊补充新的黑素细胞 [7] [8] 。

黑素干细胞呈椭圆形、无突起、不产生黑素颗粒 [9] 。黑素干细胞的生物学活性与毛发周期密切相关 [10] 。黑素干细胞通常处于静息状态,功能基因的转录水平低,只在毛囊生长期早期被激活并发生增殖、迁移和分化,一部分子代细胞留在毛囊隆突区中继续保持静息状态;另一部分则分化为黑素母细胞沿着外毛根鞘向上迁移到表皮或向下迁移到毛球,进一步分化为成熟的黑素细胞 [11] [12] 。每个成熟的黑素细胞延伸其树突,以约1:36的比例瞄准特定的角质形成细胞,形成色素单元。同时,成熟的黑素细胞生成黑色素,运输到毛干和周围的角质形成细胞,为毛发和皮肤着色 [13] 。黑素干细胞除了参与毛发周期的生理调节外,在皮肤损伤、脱毛处理、紫外线照射和电离辐射等情况下也可以被激活,进而促进黑素细胞和毛囊的再生 [14] [15] [16] 。

2.2. 调控黑素干细胞的关键信号

2.2.1. WNT信号

Wnt家族由至少19种分泌蛋白组成,富含半胱氨酸,通过G蛋白偶联受体Frizzled发挥作用。经典Wnt通路的调控过程,主要围绕β-catenin调节因子进行。当Wnt与其膜受体FZD结合后,激活胞内蛋白DVL并抑制能够降解β-Catenin的复合物形成,稳定细胞质中游离状态的β-Catenin蛋白。当积累的β-catenin浓度升高到一定程度后,会进入细胞核并与TCF/LEF转录因子结合,以调控靶基因的表达 [17] 。经典Wnt信号受体Frizzled4、Frizzled7等在黑素干细胞中表达 [18] ,且Wnt1、Wnt4和Wnt7b在整个毛囊休止期的隆突区中表达,Wnt3、Wnt6、Wnt10a和Wnt10b在隆突区也有低表达,对黑素干细胞的维持和分化是必需的 [19] 。

在胚胎发育过程中,Wnt信号在神经嵴细胞分化过程中发挥诱导作用 [20] 。Wnt信号可以通过β-catenin和LEF-1介导小眼畸形相关转录因子Mitf的转录 [21] 。Mitf是黑素细胞谱系特化的主要调控因子,通过转录激活靶基因酪氨酸酶(TYR)、酪氨酸酶相关蛋白1 (TYRP1)、多巴胺互变异构酶(DCT)和PMEL等色素基因的表达调控黑素细胞的合成黑色素的功能 [22] 。研究表明,Wnt1和Wnt3a的表达促进神经嵴细胞向黑素细胞分化 [20] [23] 。在小鼠毛囊休止期中,过表达Wnt3a和Wnt10b可促进黑素干细胞的分化,诱导隆突区色素沉着 [24] [25] 。此外,在黑素干细胞中强制表达β-catenin后激活Wnt信号,可诱导黑素干细胞分化为成熟的黑素细胞并产生黑素颗粒 [26] 。体外实验表明Wnt信号通路的抑制剂DKK1抑制黑素细胞的分化,从而降低黑素细胞的功能 [18] 。在生长早期的毛囊内靶向敲除黑素干细胞中的β-catenin会显著减少毛球中黑素细胞的数目,导致白发,但不影响隆突区中黑素干细胞的存活 [26] 。

2.2.2. EDNRB信号

Ednrb是一种G蛋白偶联受体,包含Edn1、Edn2和Edn3三种配体,通过与配体结合调控下游信号,包括PKC和MAPK等 [27] 。在毛囊中,Ednrb在黑素干细胞、黑素细胞和外根鞘细胞中表达,Edn1和Edn2在生长早期的隆突区中表达,而Edn3在生长早期的毛发基质中表达,对黑素干细胞的维持和增殖发挥重要作用 [27] [28] [29] 。

在Ednrb敲除小鼠的毛囊中,隆突区的黑素干细胞丢失,导致毛发变白 [30] 。在其配体中,只有Edn3缺失会导致黑素细胞的发育异常和白色斑点,而过度表达Edn3会诱导黑素干细胞分化和色素沉着 [31] [32] 。另外两种配体,Edn1和Edn2,也参与调控黑素干细胞分化、增殖和迁移。过度表达Edn2导致黑素干细胞过早分化并在隆突区生成黑色素 [33] ,而过度表达Edn1促进黑素干细胞分化并向表皮迁移以提供黑素细胞 [30] 。最近有研究表明Edn1比Edn3更加有效地促进人胚胎干细胞向黑素细胞转化,并维持黑素母细胞的增殖和分化 [34] 。

2.2.3. KIT信号

Kit是一种原癌基因,属于酪氨酸酶激酶受体家族的成员,通过与配体干细胞因子(SCF)结合,使其二聚化和自磷酸化并激活下游信号转导,包括PI3K、MAPK和STAT [35] 。毛囊隆突区中的黑素干细胞低水平表达Kit,而分化中的黑素细胞和成熟的黑素细胞高水平表达Kit,其对黑素干细胞的分化、增殖和毛干色素沉着是必要的 [15] 。

研究发现Kit或SCF突变的小鼠表现出毛发着色缺陷,阻断了黑素细胞的发育,还会导致早期造血失败,纯合子胚胎致死 [36] [37] 。同样,注射Kit中和抗体也会阻断小鼠毛囊中黑素干细胞的分化和增殖,并降低黑素细胞的生存,导致头发变白 [38] 。相反,体外实验表明过度表达SCF促进人黑素细胞的增殖和迁移 [39] [40] 。

2.2.4. TGF-β信号

人类中存在至少33个TGF-β家族蛋白,参与多种细胞的生长、迁移、增殖、凋亡等过程。TGF-β是一个大家族的生长因子,目前已经鉴定出了三个TGF-β亚型:TGF-β1、TGF-β2和TGF-β3。在TGF-β与I型和II型受体结合后形成异二聚体复合物,诱导II型受体磷酸化并激活I型受体,磷酸化Smad2/3形成复合物,在细胞核内聚集并作为转录因子发挥转录调控作用 [41] [42] 。TGF-β1和TGF-β2在毛囊生早期晚期的隆突区中表达,TGF-β信号被激活以磷酸化Smad2,是维持黑素干细胞的关键生态位因子之一 [43] 。

在体外,TGF-β不仅诱导可逆的细胞周期停滞,还可以通过下调黑素细胞分化的关键转录因子MITF及其下游黑素合成相关基因来促进黑素细胞的不成熟。在体内,当黑素干细胞在毛发周期中重新进入静息状态时,TGF-β信号传导被激活。此外,靶向敲除黑素细胞中TGF-β II型受体(TβRII)会诱导隆突区中黑素干细胞的过早分化和丢失,并导致头发灰白 [42] 。然而最近的研究表明,在斑马鱼黑素细胞再生过程中经典的TGF-β/BMP途径的功能激活促进了黑素细胞再生 [44] 。因此,TGF-β信号通路在黑素干细胞的激活方面可能具有双重功能。

2.2.5. NOTCH信号

Notch信号是一种高度保守,决定细胞命运的重要信号通路。哺乳动物拥有四种不同的Notch受体,它们通过细胞与细胞之间的相互作用与特定的配体(Delta-like ligands, DLL1/3/4; Jagged ligands, JAG1/2)结合。一旦被激活,Notch胞内结构域(NICD1)被酶切水解,并从细胞膜上易位到细胞核中,与转录因子RBP-J结合并激活下游靶基因 [45] 。Nishikawa等人发现,E16.5胚胎黑素母细胞大量表达Notch蛋白家族,包括Notch1受体和Jagged2配体,以及Notch靶基因hes1、hes5和hey1,且在隆起区的黑素干细胞对NICD1和hes1都呈阳性反应,其参与维持黑素干细胞的特性 [46] 。

黑素细胞中Notch1和Notch2靶向缺失的小鼠在出生后,第一个毛发周期具有正常的色素模式,但从第二个毛发周期开始变白,毛囊隆突区中黑素干细胞逐渐丢失。Notch1/2的特异性抑制剂GSI的处理也会导致黑素细胞的凋亡和黑素干细胞的丢失 [47] 。同样,黑素细胞特异性缺失Notch信号的下游转录因子RBP-J,也会导致类似的头发变白 [46] 。

2.2.6. MC1R信号

Mc1R是一种G蛋白偶联受体,在人体组织和细胞中广泛表达,在色素沉着中发挥重要作用。当其配体α-MSH激活Mc1R后,通过与腺苷环化酶相互作用产生第二信使cAMP,并激活下游信号,如cAMP依赖的蛋白激酶(PKA) [15] [48] 。在毛囊中,Mc1R在整个毛发周期的生长阶段特异性地表达在所有黑素细胞的表面,促进真黑素生成 [15] 。

在Mc1R突变小鼠中,真黑素生成严重减少并导致红发的表型,而对黑素干细胞没有影响,能够在毛囊生长期重新填充黑素细胞 [16] [49] 。有趣的是,UVB照射诱导的黑素干细胞向表皮迁移的行为在Mc1R突变后被阻断,且可以通过Edn1的过表达来挽救,表明Mc1R信号在黑素干细胞迁移中发挥重要作用 [30] [50] 。

2.3. 其他细胞对黑素干细胞的影响

2.3.1. 毛囊干细胞

毛囊干细胞和黑素干细胞共同存在于毛囊隆突区,在生长期早期增殖、分化。毛囊干细胞和黑素干细胞之间的相互作用对毛发再生和色素沉着具有重要作用 [50] 。Rabbani等人利用毛囊干细胞和黑素干细胞的转基因小鼠发现,毛囊干细胞除了自发激活Wnt信号,还能通过分泌Wnts来激活邻近黑素干细胞的Wnt信号并诱导其分化。同时,毛囊干细胞在Wnt信号作用下可以分泌Edn1和Edn2,与黑素干细胞表面的Ednr结合并诱导其分化 [26] 。毛囊干细胞还通过分泌的TGF-β信号来维持对黑素干细胞的微环境 [42] 。另外,毛囊干细胞自身异常也会导致黑素干细胞的信号紊乱。在毛囊干细胞,核因子I/B (NFIB)和RBP-J的缺失会破坏生态位,导致黑素干细胞的异位分化 [51] [52] 。COL17A1是一种跨膜胶原蛋白,在毛囊干细胞中高表达,而不表达于黑素干细胞。COL17A1突变小鼠不仅导致毛囊干细胞停止静息状态,也致使黑素干细胞过早分化并产生白发。在COL17A1缺失的小鼠中,在K14启动子的控制下过表达COL17A1,可以挽救这种毛发灰白的表型 [52] 。

2.3.2. 毛乳头细胞

毛乳头细胞位于毛囊的基底部,属于成纤维细胞,在毛囊发育和生长周期的调节中发挥重要作用 [53] 。黑素干细胞被激活后从隆突区进入外毛根鞘,在毛乳头信号的作用下会向下迁移到毛球部并分化为成熟的黑素细胞。基于毛乳头细胞与黑素干细胞被基底膜分隔,其对黑素干细胞的调控主要是通过分泌细胞因子来实现。毛乳头细胞可以分泌SCF与黑素干细胞膜表面的Kit受体结合,激活Kit信号通路后调控黑素干细胞的分化,亦可以通过Wnt/β-catenin信号参与调控黑素干细胞的增殖和分化 [26] [54] 。

2.3.3. 角质形成细胞

角质形成细胞是表皮细胞的主要组成部分,在分化过程中会形成角蛋白,参与表皮和毛囊的形成。角质形成细胞和黑素细胞处于紧密的解剖和功能关系。角质形成细胞可以接收临近黑素细胞生成的黑素颗粒为皮肤和毛发着色,还可以提供一系列的旁分泌因子,调节黑素细胞的存活、增殖和分化 [55] [56] 。有研究发现,在小鼠发育过程中的角质形成细胞过表达SCF,可以促进黑素细胞的分化、增殖和迁移,并导致大量的表皮细胞和色素沉着 [57] 。角质形成细胞还可以生成Edn1,与黑素干细胞表面的Ednr结合调控黑素干细胞的分化与增殖 [58] 。此外,角质形成细胞可以分泌TGF-β,通过下调MITF的表达使黑素干细胞维持静息状态 [59] 。

3. 黑素干细胞和白癜风

3.1. 白癜风及其复色

白癜风是一种常见的后天获得性、慢性色素脱失性疾病,临床特征是局限性或泛发性皮肤黏膜色素完全脱失。白癜风的发病因素众多,主要原因是CD8+ T细胞异常攻击自体的黑素细胞,导致皮损区的黑素细胞缺失和/或功能障碍,但黑素干细胞仍然存在 [60] [61] 。这可能是因为毛囊隆突区具有相对免疫赦免性,且周围有丰富的血管和神经支配,处于复杂的皮肤微环境,能够保护黑素干细胞免受自身免疫系统的攻击 [62] 。

白癜风的治疗方式主要涉及物理治疗、药物治疗、手术治疗和联合治疗。根据不同的治疗手段,白癜风病人出现不同的复色模式,包括毛囊周围复色模式、边缘复色模式、弥漫复色模式和混合模式 [60] 。毛囊周围复色模式是白癜风治疗后最常见的一种复色模式,其特征是形成以毛囊为中心的点状色素岛,逐渐向周围扩展并和正常颜色的皮肤融合,因此缺乏毛囊的黏膜和掌跖等部位较难复色 [63] 。这也提示了再生的黑素细胞来源于毛囊隆突区的黑素干细胞池。

3.2. 黑素干细胞在色素再沉着中的作用

临床上常用窄谱中波紫外线(NB-UVB)治疗白癜风,复色方式主要是毛囊周围型。UVB诱导色素再沉着的过程包括黑素干细胞的活化、迁移、增殖和分化,对白癜风皮损区黑素细胞的再生是不可或缺的 [6] 。已有研究证实,在UVB照射后,毛囊隆突区的黑素干细胞被直接激活,并迁移到隆突区的上方,同时分化为黑素母细胞并处于过渡–扩增状态。此时位于上隆突区的黑素母细胞沿着外毛根鞘向毛囊口周围的表皮迁移并增殖,在表皮基底层分化为黑素细胞。成熟的黑素细胞形成黑素小体并具有合成黑色素的能力,产生的黑色素用于皮损区的重新着色。在不同动物或人类色素沉着的过程中,黑素细胞的分化已被证明伴随着增殖和/或迁移,然而其对白癜风治疗的具体意义有待探索 [14] [64] 。

UVB辐射导致色素沉着的分子机制尚未完全清楚,但已经确定了几个重要的信号通路。Chou等人发现暴露于UVB后,黑素干细胞以Mc1R依赖的方式迁移至表皮,并分化为功能性的表皮黑素细胞 [50] 。还有研究表明,UVB照射会诱导角质形成细胞分泌Wnt7a,通过激活Wnt信号致使黑素干细胞向成熟的黑细胞分化,在此过程中表皮表达的Kit配体促进了黑素干细胞向表皮迁移 [65] 。UVB光疗还可以导致TGF-β的表达减少,使黑素干细胞更容易被激活 [16] 。以上研究显示,激活毛囊隆突区中休眠的黑素干细胞并改善皮肤微环境有助于白癜风皮损区黑素细胞的再生,是实现色素再沉着的关键。

4. 总结与展望

白癜风的发病机制复杂,尚无治疗方法能够确保白癜风完全治愈,其大都围绕终止黑素细胞损伤和弥补黑素细胞数量不足这两点来改善症状。黑素干细胞作为成体干细胞,在个体功能细胞受损或死亡的情况下具有重新进入分化过程,形成功能性细胞的能力。近年来,越来越多的学者关注到黑素干细胞治疗白癜风的潜能。在这篇综述中,我们总结了黑素干细胞的起源和特性,分子调控机制和皮肤微环境中细胞间的串扰。同时,我们还指出在白癜风治疗中UVB照射激活黑素干细胞的过程及色素再沉着的机制。对黑素干细胞的进一步了解,丰富了我们对于黑素细胞再生调控网络的认识,并有助于开发通过激活黑素干细胞治疗白癜风的药物。

NOTES

*通讯作者。

参考文献

[1] Xin, T., Greco, V. and Myung, P. (2016) Hardwiring Stem Cell Communication through Tissue Structure. Cell, 164, 1212-1225.
https://doi.org/10.1016/j.cell.2016.02.041
[2] Lee, J.H. and Fisher, D.E. (2014) Melanocyte Stem Cells as Potential Therapeutics in Skin Disorders. Expert Opinion on Biological Therapy, 14, 1569-1579.
https://doi.org/10.1517/14712598.2014.935331
[3] Lin, J.Y. and Fisher, D.E. (2007) Melanocyte Biology and Skin Pigmentation. Nature, 445, 843-850.
https://doi.org/10.1038/nature05660
[4] Wang, Z.H., Liu, L.P. and Zheng, Y.W. (2022) Melanocyte Stem Cells in Skin Diseases and Their Potential in Cell-Based Therapy. Histology and Histopathology, 37, 937-953.
[5] Etchevers, H.C., Dupin, E. and Le Douarin, N.M. (2019) The Diverse Neural Crest: From Embryology to Human Pathology. Development, 146, Dev169821.
https://doi.org/10.1242/dev.169821
[6] Li, A. (2014) The Biology of Melanocyte and Melanocyte Stem Cell. Acta Biochimica et Biophysica Sinica (Shanghai), 46, 255-260.
https://doi.org/10.1093/abbs/gmt145
[7] O’Sullivan, J., Nicu, C., Picard, M., et al. (2021) The Biology of Human Hair Greying. Biological reviews of the Cambridge Philosophical Society, 96, 107-128.
https://doi.org/10.1111/brv.12648
[8] Qiu, W., Chuong, C.M. and Lei, M. (2019) Regulation of Melanocyte Stem Cells in the Pigmentation of Skin and Its Appendages: Biological Patterning and Therapeutic Potentials. Experimental Dermatology, 28, 395-405.
https://doi.org/10.1111/exd.13856
[9] Yang, K., Chen, J., Jiang, W., et al. (2012) Conditional Immortalization Establishes a Repertoire of Mouse Melanocyte Progenitors with Distinct Melanogenic Differentiation Potential. Journal of Investigative Dermatology, 132, 2479-2483.
https://doi.org/10.1038/jid.2012.145
[10] Nishimura, E.K. (2011) Melanocyte Stem Cells: A Melanocyte Reservoir in Hair Follicles for Hair and Skin Pigmentation. Pigment Cell & Melanoma Research, 24, 401-410.
https://doi.org/10.1111/j.1755-148X.2011.00855.x
[11] Osawa, M., Egawa, G., Mak, S.S., et al. (2005) Molecular Characterization of Melanocyte Stem Cells in Their Niche. Development, 132, 5589-5599.
https://doi.org/10.1242/dev.02161
[12] Zhang, B., Ma, S., Rachmin, I., et al. (2020) Hyperactivation of Sympathetic Nerves Drives Depletion of Melanocyte Stem Cells. Nature, 577, 676-681.
https://doi.org/10.1038/s41586-020-1935-3
[13] Cordero, R. and Casadevall, A. (2020) Melanin. Current Biology, 30, R142-R143.
https://doi.org/10.1016/j.cub.2019.12.042
[14] Allouche, J., Rachmin, I., Adhikari, K., et al. (2021) NNT Mediates Redox-Dependent Pigmentation via a UVB-and MITF-Independent Mechanism. Cell, 184, 4268-4283.E20.
https://doi.org/10.1016/j.cell.2021.06.022
[15] Li, H. and Hou, L. (2018) Regulation of Melanocyte Stem Cell Behavior by the Niche Microenvironment. Pigment Cell & Melanoma Research, 31, 556-569.
https://doi.org/10.1111/pcmr.12701
[16] Yardman-Frank, J.M. and Fisher, D.E. (2021) Skin Pigmentation and Its Control: From Ultraviolet Radiation to Stem Cells. Experimental Dermatology, 30, 560-571.
https://doi.org/10.1111/exd.14260
[17] Sutton, G., Kelsh, R.N. and Scholpp, S. (2021) Review: The Role of Wnt/β-Catenin Signalling in Neural Crest Development in Zebrafish. Frontiers in Cell and Developmental Biology, 9, Article ID: 782445.
https://doi.org/10.3389/fcell.2021.782445
[18] Lim, X., Tan, S.H., Yu, K.L., et al. (2016) Axin2 Marks Quiescent Hair Follicle Bulge Stem Cells That Are Maintained by Autocrine Wnt/β-Catenin Signaling. Proceedings of the National Academy of Sciences of the United States of America, 113, E1498-E1505.
https://doi.org/10.1073/pnas.1601599113
[19] Yamada, T., Akamatsu, H., Hasegawa, S., et al. (2010) Melanocyte Stem Cells Express Receptors for Canonical Wnt-Signaling Pathway on Their Surface. Biochemical and Biophysical Research Communications, 396, 837-842.
https://doi.org/10.1016/j.bbrc.2010.04.167
[20] Dunn, K.J., Williams, B.O., Li, Y., et al. (2000) Neural Crest-Directed Gene Transfer Demonstrates Wnt1 Role in Melanocyte Expansion and Differentiation during Mouse Development. Proceedings of the National Academy of Sciences of the United States of America, 97, 10050-10055.
https://doi.org/10.1073/pnas.97.18.10050
[21] Hari, L., Miescher, I., Shakhova, O., et al. (2012) Temporal Control of Neural Crest Lineage Generation by Wnt/β-Catenin Signaling. Development, 139, 2107-2117.
https://doi.org/10.1242/dev.073064
[22] Cichorek, M., Wachulska, M., Stasiewicz, A., et al. (2013) Skin Melanocytes: Biology and Development. Postępy Dermatologii i Alergologii, 30, 30-41.
https://doi.org/10.5114/pdia.2013.33376
[23] Dunn, K.J., Brady, M., Ochsenbauer-Jambor, C., et al. (2005) WNT1 and WNT3a Promote Expansion of Melanocytes through Distinct Modes of Action. Pigment Cell Research, 18, 167-180.
https://doi.org/10.1111/j.1600-0749.2005.00226.x
[24] Guo, H., Yang, K., Deng, F., et al. (2012) Wnt3a Promotes Melanin Synthesis of Mouse Hair Follicle Melanocytes. Biochemical and Biophysical Research Communications, 420, 799-804.
https://doi.org/10.1016/j.bbrc.2012.03.077
[25] Ye, J., Yang, T., Guo, H., et al. (2013) Wnt10b Promotes Differentiation of Mouse Hair Follicle Melanocytes. International Journal of Medical Sciences, 10, 691-698.
https://doi.org/10.7150/ijms.6170
[26] Rabbani, P., Takeo, M., Chou, W., et al. (2011) Coordinated Activation of Wnt in Epithelial and Melanocyte Stem Cells Initiates Pigmented Hair Regeneration. Cell, 145, 941-955.
https://doi.org/10.1016/j.cell.2011.05.004
[27] Hou, L. and Pavan, W.J. (2008) Transcriptional and Signaling Regulation in Neural Crest Stem Cell-Derived Melanocyte Development: Do All Roads Lead to Mitf. Cell Research, 18, 1163-1176.
https://doi.org/10.1038/cr.2008.303
[28] Li, H., Fan, L., Zhu, S., et al. (2017) Epilation Induces Hair and Skin Pigmentation through an EDN3/EDNRB-Dependent Regenerative Response of Melanocyte Stem Cells. Scientific Reports, 7, Article No. 7272.
https://doi.org/10.1038/s41598-017-07683-x
[29] Rezza, A., Wang, Z., Sennett, R., et al. (2016) Signaling Networks among Stem Cell Precursors, Transit-Amplifying Progenitors, and Their Niche in Developing Hair Follicles. Cell Reports, 14, 3001-3018.
https://doi.org/10.1016/j.celrep.2016.02.078
[30] Takeo, M., Lee, W., Rabbani, P., et al. (2016) EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling. Cell Reports, 15, 1291-1302.
https://doi.org/10.1016/j.celrep.2016.04.006
[31] Endou, M., Aoki, H., Kobayashi, T., et al. (2014) Prevention of Hair Graying by Factors That Promote the Growth and Differentiation of Melanocytes. The Journal of Dermatology, 41, 716-723.
https://doi.org/10.1111/1346-8138.12570
[32] Yuriguchi, M., Aoki, H., Taguchi, N., et al. (2016) Pigmentation of Regenerated Hairs after Wounding. Journal of Dermatological Science, 84, 80-87.
https://doi.org/10.1016/j.jdermsci.2016.07.004
[33] Chang, C.Y., Pasolli, H.A., Giannopoulou, E.G., et al. (2013) NFIB Is a Governor of Epithelial-Melanocyte Stem Cell Behaviour in a Shared Niche. Nature, 495, 98-102.
https://doi.org/10.1038/nature11847
[34] Zeng, X., Lv, H., Jin, Y., et al. (2024) Enhanced Quality of HESC-Derived Melanocytes through Modified Concentration of Endothelin-1. Experimental Dermatology, 33, E15004.
https://doi.org/10.1111/exd.15004
[35] Yun, C.Y., Roh, E., Kim, S.H., et al. (2020) Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation. Theranostics, 10, 340-352.
https://doi.org/10.7150/thno.39066
[36] Cable, J., Jackson, I.J. and Steel, K.P. (1995) Mutations at the W Locus Affect Survival of Neural Crest-Derived Melanocytes in the Mouse. Mechanisms of Development, 50, 139-150.
https://doi.org/10.1016/0925-4773(94)00331-G
[37] Wehrle-Haller, B. and Weston, J.A. (1995) Soluble and Cell-Bound Forms of Steel Factor Activity Play Distinct Roles in Melanocyte Precursor Dispersal and Survival on the Lateral Neural Crest Migration Pathway. Development, 121, 731-742.
https://doi.org/10.1242/dev.121.3.731
[38] Hachiya, A., Sriwiriyanont, P., Kobayashi, T., et al. (2009) Stem Cell Factor-KIT Signalling Plays a Pivotal Role in Regulating Pigmentation in Mammalian Hair. The Journal of Pathology, 218, 30-39.
https://doi.org/10.1002/path.2503
[39] Jeon, S., Kim, N.H., Kim, J.Y., et al. (2009) Stem Cell Factor Induces ERM Proteins Phosphorylation through PI3K Activation to Mediate Melanocyte Proliferation and Migration. Pigment Cell & Melanoma Research, 22, 77-85.
https://doi.org/10.1111/j.1755-148X.2008.00519.x
[40] Wang, D.G., Xu, X.H., Ma, H.J., et al. (2013) Stem Cell Factor Combined with Matrix Proteins Regulates the Attachment and Migration of Melanocyte Precursors of Human Hair Follicles in Vitro. Biological and Pharmaceutical Bulletin, 36, 1317-1325.
https://doi.org/10.1248/bpb.b13-00172
[41] Massagué, J. (2008) TGFbeta in Cancer. Cell, 134, 215-230.
https://doi.org/10.1016/j.cell.2008.07.001
[42] Nishimura, E.K., Suzuki, M., Igras, V., et al. (2010) Key Roles for Transforming Growth Factor Beta in Melanocyte Stem Cell Maintenance. Cell Stem Cell, 6, 130-140.
https://doi.org/10.1016/j.stem.2009.12.010
[43] Tumbar, T., Guasch, G., Greco, V., et al. (2004) Defining the Epithelial Stem Cell Niche in Skin. Science, 303, 359-363.
https://doi.org/10.1126/science.1092436
[44] Katkat, E., Demirci, Y., Heger, G., et al. (2023) Canonical Wnt and TGF-β/BMP Signaling Enhance Melanocyte Regeneration but Suppress Invasiveness, Migration, and Proliferation of Melanoma Cells. Frontiers in Cell and Developmental Biology, 11, Article ID: 1297910.
https://doi.org/10.3389/fcell.2023.1297910
[45] Liu, J., Fukunaga-Kalabis, M., Li, L., et al. (2014) Developmental Pathways Activated in Melanocytes and Melanoma. Archives of Biochemistry and Biophysics, 563, 13-21.
https://doi.org/10.1016/j.abb.2014.07.023
[46] Moriyama, M., Osawa, M., Mak, S.S., et al. (2006) Notch Signaling via Hes1 Transcription Factor Maintains Survival of Melanoblasts and Melanocyte Stem Cells. Journal of Cell Biology, 173, 333-339.
https://doi.org/10.1083/jcb.200509084
[47] Kumano, K., Masuda, S., Sata, M., et al. (2008) Both Notch1 and Notch2 Contribute to the Regulation of Melanocyte Homeostasis. Pigment Cell & Melanoma Research, 21, 70-78.
https://doi.org/10.1111/j.1755-148X.2007.00423.x
[48] Wolf Horrell, E.M., Boulanger, M.C. and D’Orazio, J.A. (2016) Melanocortin 1 Receptor: Structure, Function, and Regulation. Frontiers in Genetics, 7, Article No. 95.
https://doi.org/10.3389/fgene.2016.00095
[49] Mitra, D., Luo, X., Morgan, A., et al. (2012) An Ultraviolet-Radiation-Independent Pathway to Melanoma Carcinogenesis in the Red Hair/Fair Skin Background. Nature, 491, 449-453.
https://doi.org/10.1038/nature11624
[50] Chou, W.C., Takeo, M., Rabbani, P., et al. (2013) Direct Migration of Follicular Melanocyte Stem Cells to the Epidermis after Wounding or UVB Irradiation Is Dependent on Mc1r Signaling. Nature Medicine, 19, 924-929.
https://doi.org/10.1038/nm.3194
[51] Lu, Z., Xie, Y., Huang, H., et al. (2020) Hair Follicle Stem Cells Regulate Retinoid Metabolism to Maintain the Self-Renewal Niche for Melanocyte Stem Cells. Elife, 9, e52712.
https://doi.org/10.7554/eLife.52712
[52] Tanimura, S., Tadokoro, Y., Inomata, K., et al. (2011) Hair Follicle Stem Cells Provide a Functional Niche for Melanocyte Stem Cells. Cell Stem Cell, 8, 177-187.
https://doi.org/10.1016/j.stem.2010.11.029
[53] Rendl, M., Lewis, L. and Fuchs, E. (2005) Molecular Dissection of Mesenchymal-Epithelial Interactions in the Hair Follicle. PLOS Biology, 3, E331.
https://doi.org/10.1371/journal.pbio.0030331
[54] Aoki, H., Hara, A., Motohashi, T., et al. (2011) Protective Effect of Kit Signaling for Melanocyte Stem Cells against Radiation-Induced Genotoxic Stress. Journal of Investigative Dermatology, 131, 1906-1915.
https://doi.org/10.1038/jid.2011.148
[55] Hoath, S.B. and Leahy, D.G. (2003) The Organization of Human Epidermis: Functional Epidermal Units and Phi Proportionality. Journal of Investigative Dermatology, 121, 1440-1446.
https://doi.org/10.1046/j.1523-1747.2003.12606.x
[56] Osawa, M. (2008) StemBook.
[57] Nishimura, E.K., Jordan, S.A., Oshima, H., et al. (2002) Dominant Role of the Niche in Melanocyte Stem-Cell Fate Determination. Nature, 416, 854-860.
https://doi.org/10.1038/416854a
[58] Ma, H.J., Zhu, W.Y., Wang, D.G., et al. (2006) Endothelin-1 Combined with Extracellular Matrix Proteins Promotes the Adhesion and Chemotaxis of Amelanotic Melanocytes from Human Hair Follicles in Vitro. Cell Biology International, 30, 999-1006.
https://doi.org/10.1016/j.cellbi.2006.07.007
[59] Lei, T.C. and Hearing, V.J. (2020) Deciphering Skin Re-Pigmentation Patterns in Vitiligo: An Update on the Cellular and Molecular Events Involved. Chinese Medical Journal (England), 133, 1231-1238.
https://doi.org/10.1097/CM9.0000000000000794
[60] Frisoli, M.L., Essien, K. and Harris, J.E. (2020) Vitiligo: Mechanisms of Pathogenesis and Treatment. Annual Review of Immunology, 38, 621-648.
https://doi.org/10.1146/annurev-immunol-100919-023531
[61] Xu, Z., Chen, D., Hu, Y., et al. (2022) Anatomically Distinct Fibroblast Subsets Determine Skin Autoimmune Patterns. Nature, 601, 118-124.
https://doi.org/10.1038/s41586-021-04221-8
[62] Meyer, K.C., Klatte, J.E., Dinh, H.V., et al. (2008) Evidence That the Bulge Region Is a Site of Relative Immune Privilege in Human Hair Follicles. British Journal of Dermatology, 159, 1077-1085.
https://doi.org/10.1111/j.1365-2133.2008.08818.x
[63] Yang, Y.S., Cho, H.R., Ryou, J.H., et al. (2010) Clinical Study of Repigmentation Patterns with either Narrow-Band Ultraviolet B (NBUVB) or 308 Nm Excimer Laser Treatment in Korean Vitiligo Patients. International Journal of Dermatology, 49, 317-323.
https://doi.org/10.1111/j.1365-4632.2009.04332.x
[64] Birlea, S.A., Costin, G.E., Roop, D.R., et al. (2017) Trends in Regenerative Medicine: Repigmentation in Vitiligo through Melanocyte Stem Cell Mobilization. Medicinal Research Reviews, 37, 907-935.
https://doi.org/10.1002/med.21426
[65] Yamada, T., Hasegawa, S., Inoue, Y., et al. (2013) Wnt/β-Catenin and Kit Signaling Sequentially Regulate Melanocyte Stem Cell Differentiation in UVB-Induced Epidermal Pigmentation. Journal of Investigative Dermatology, 133, 2753-2762.
https://doi.org/10.1038/jid.2013.235