The regulation of melanocyte stem cells by Wnt signaling

摘要 我们的长期目标是了解黑素细胞干细胞的准确位置和分子调控。 (MSCs)，特别强调Wnt通路在调节正常和异常MSCs中的作用(S)。 我们以前的研究报告毛囊内的McSCs(HF McSCs)可以促进头发色素沉着。 并具有通过激活Wnt信号产生表皮黑素细胞的潜能。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信号转导 与致癌基因突变引发的机制的串扰，以驱动黑色素瘤的发生。尽管如此，一个 McSCs的表皮来源通常被认为是皮肤MC的最有可能的贡献者，皮肤 色素沉着和大多数色素沉着障碍，包括白癜风、炎症后色素沉着、 以及致命的皮肤癌黑色素瘤，这是一种源于人类毛囊间皮肤表皮的疾病。因此， 在上一个资助期，我们问了一个基本问题：皮肤中是否也存在麦克斯卡干细胞？ 是表皮吗？“要解决这一问题，需要检查表皮黑素细胞的自我可持续性和 再生能力不受高频干细胞的污染，有可能产生巨噬细胞，在 尤其是在皮肤受伤之后。该领域的主要挑战是缺乏针对黑素细胞的工具 区分正常皮肤中大量毛囊的表皮间充质干细胞(EpMcSCs)和高频间充质干细胞 现在时。在这里，我们创造了一种新的小鼠模型，OCA2-creERT，它只针对有色的表皮 黑素细胞而不以HF McSCs为靶点。我们已经使用这个新的工具来证明OCA2+表皮 黑素细胞是有色的，但自我维持，并具有在动态平衡和 在UVB照射等生理刺激下进行增殖和分化。这些发现使我们得以 假设OCA2+MC具有干细胞/祖细胞的特征并执行 皮肤中的再生功能不依赖于HF McSCs。这种新模式为我们提供了必要的 在下一个授权期，解决OCA2+MC如何拥有再生各种 皮肤黑素细胞长期保持自我更新能力(Aim1)，Wnt信号通路如何 与其他关键信号通路(AIM2)协同调节它们的再生行为 OCA2+的表皮黑素细胞可作为黑色素瘤转化潜能的色素痣的细胞来源 在Wnt信号(Aim3)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).