The regulation of melanocyte stem cells by Wnt signaling

总结 我们的长期目标是了解黑素细胞干细胞的精确定位和分子调控 本论文的重点是Wnt通路在调节正常和异常McSCs中的作用。 我们以前的研究报道，毛囊内的McSCs（HF McSCs）可以促进毛发色素沉着 并且具有通过激活Wnt信号传导产生表皮黑素细胞的潜力。最近， 我们报道了致癌的HF McSCs可以转化为黑色素瘤，并证明了Wnt信号通路 与致癌突变引起的机制的交叉，以驱动黑色素瘤的发生。尽管如此， McSC的表皮来源通常被认为是皮肤MCs、皮肤 色素沉着和大多数色素沉着疾病，包括白癜风，炎症后色素沉着过度， 以及致命的皮肤癌黑色素瘤，这是一种由人类毛囊间皮肤表皮引起的疾病。因此，在本发明中， 在上一个资助期间，我们提出了一个基本问题：“皮肤中是否也存在MCSC 表皮？”解决这一问题需要检查表皮黑素细胞的自我维持能力， 再生能力而不污染HF McSCs，其具有产生MC的潜力， 至少在皮肤受伤后。该领域的主要挑战是缺乏黑素细胞特异性工具， 区分正常皮肤中的表皮McSC（epMcSC）和HF McSC，在正常皮肤中， 礼物在这里，我们已经创建了一种新的小鼠模型，OCA 2-creERT，它只针对色素沉着的表皮 黑素细胞而不靶向HF McSCs。我们已经使用这种新的工具来证明OCA 2+表皮 黑素细胞是色素沉着的，但能自我维持，并具有在体内平衡期间再生的能力， 在生理刺激如UVB照射后增殖和分化。这些发现使我们 假设Oca 2 + MC具有干细胞/祖细胞特征， 皮肤中的再生功能独立于HF McSCs。这种新模式为我们提供了必要的 工具来解决，在下一个授予期，Oca 2 + MC如何拥有再生各种 皮肤黑素细胞，同时保持自我更新能力的长期（Aim 1），如何Wnt信号通路 与其他关键信号通路（Aim 2）合作调节其再生行为， OCA 2+表皮黑素细胞可能是痣的细胞来源，具有黑色素瘤转化的潜力 在Wnt信号传导（Aim 3）的影响下。

Summary Our long-term goal is to understand the precise location and molecular regulation of melanocyte stem cells (McSCs), with a special emphasis on the role(s) of the Wnt pathway in regulating normal and abnormal McSCs. Our previous studies reported that McSCs within the hair follicle (HF McSCs) can contribute to hair pigmentation and possess the potential to produce epidermal melanocytes through activation of Wnt signaling. More recently, we reported that oncogenic HF McSCs can transform into melanoma and demonstrated that Wnt signaling crosstalks with mechanisms elicited by oncogenic mutations to drive melanomagenesis. Nonetheless, an epidermal source of McSCs has been commonly proposed as the most likely contributor to skin MCs, skin pigmentation and the majority of pigmentation disorders, including vitiligo, post-inflammatory hyperpigmentation, and the deadly skin cancer melanoma, disorders that arise from interfollicular skin epidermis in humans. Thus, during the last funding period, we asked a fundamental question “do McSCs also exist within the skin epidermis?” Addressing this requires the examination of epidermal melanocytes for their self-sustainability and regenerative capacities without contamination of HF McSCs, which possess the potential to give rise to MCs, at least after skin wounding. The major challenge in the field has been the lack of a melanocyte-specific tool to distinguish epidermal McSCs (epMcSCs) from HF McSCs in normal skin where numerous hair follicles are present. Here, we have created a novel mouse model, OCA2-creERT, that solely targets pigmented epidermal melanocytes without targeting HF McSCs. We have used this novel tool to demonstrate that OCA2+ epidermal melanocytes are pigmented, yet self-sustaining, and possess the ability to regenerate during homeostasis and proliferate and differentiate following physiological stimuli like UVB irradiation. These findings have led us to hypothesize that Oca2+ MCs possess characteristics of stem cell/progenitor cells and perform regenerative functions in the skin independent of HF McSCs. This new model provides us with the necessary tools to address, in the next granting period, how Oca2+ MCs possess the lineage capacity to regenerate various skin melanocytes while retaining a self-renewing capacity long-term (Aim1), how the Wnt signaling pathway regulates their regenerative behavior in collaboration with other key signaling pathways (Aim2) and whether OCA2+ epidermal melanocytes can be a cellular source for nevi with a potential for melanoma transformation under the influence of Wnt signaling (Aim3).