毛囊黑色素干细胞通过MC1R/cAMP/TGF-β活化成纤维细胞在病理性瘢痕形成中的作用

Pathological scar is one of the most common complication of wound healing, which is closely connected with the skin color. Melanocyte stem cells in the hair follicles participate in the process of wound healing through differentiation and migration from hair follicle to the epidermis. However, it's role in scar formation is not well charted yet. Previous studies have shown that skin pigmentation was started and centered on the hair follicles, and there was an activation of MC1R signaling in the process of wound healing, in which melanocyte stem cells in the hair follicles were involved. Moreover, α-MSH, as the ligand of MC1R, was expressed higher in human pathologic scar tissue compared to in the normal skin, which could obviously elevate the expression level of TGFβ, and then, the fibroblasts were activated. The investigation on the phenomenon that metabolism of pigment participates in the activation of fibroblast supplies a novel idea to explore the mechanism of pathological scar. In this process, the interaction mechanism between fibroblast and melanocyte stem cells in the hair follicles has not been elucidated. In this study, we attempt to investigate the effect of the migration and differentiation of melanocyte stem cells in the hair follicles on the activation of fibroblast by hair model and pathological scar mouse model, which can provide a novel theoretical and experimental basis to elucidate the formation of pathological scar.

病理性瘢痕作为创面愈合后最常见的并发症之一，其发生与皮肤色素有密切关系。毛囊黑色素干细胞可通过分化、迁移至表皮，参与创面修复的过程，但是与瘢痕形成的关系仍不明确。前期研究显示，皮肤色素再生以毛囊为中心，且在毛囊黑色素干细胞参与创面愈合的过程中，存在MC1R信号的激活，而病理性瘢痕中MC1R配体--αMSH的表达增强，并且可明显促进TGFβ的分泌，进一步促发成纤维细胞的活化，这种色素代谢参与成纤维细胞活化的研究为探索病理性瘢痕的发生机制提供了新的思路。但在这个过程中，毛囊黑色素干细胞与成纤维细胞间的相互作用机制还不甚明确。本研究拟通过建立微小毛发模型及病理性瘢痕小鼠模型，探究毛囊黑色素干细胞的迁移、分化对成纤维细胞活化的影响及作用途径，这将为阐明病理性瘢痕的形成机制提供新的理论和实验依据。

研究背景：病理性瘢痕是人类皮肤真皮损伤后，以成纤维细胞（Fb）过度增殖和细胞外基质（如胶原等）过度沉积为特征的皮肤纤维化疾病。以往研究证实，在瘢痕疙瘩表皮层和瘢痕层中α-MSH表达增强，且一定剂量的α-MSH可明显促进皮肤成纤维细胞分泌TGF-β，促进成纤维细胞的生长与增殖。色素代谢与病理性瘢痕的形成具有密切联系。α-Mangostin是一种天然产物，常用于痤疮和皮肤癌的局部治疗。此前研究发现α-Mangostin在10µM浓度时对人黑色素细胞（HEM）有抗增殖活性能力。这可能揭示了α-Mangostin对色素沉着及病理性瘢痕的治疗特性。.研究内容：本研究提出假说为在病理性瘢痕形成的过程中毛囊黑色素干细胞分化、迁移、促进上皮再生及色素形成，并影响成纤维细胞的活化程度及抑制其凋亡，内在机制可能与MC1R/cAMP及其下游信号的激活参与调节TGFβ信号通路作用有关。本研究通过给予UVB照射刺激或使用靶向抑制药物干预MC1R/cAMP，及其下游RAS、PI3K信号通路，观察TGFβ的表达改变及成纤维细胞的增殖、活化程度；验证HEM参与病理性瘢痕形成的分子机制。同时研究α-Mangostin抑制黑色素合成的分子通路机制，并探究其脱色素效果。 .重要结果与关键数据：1. UVB刺激下囊隆突区干细胞向表皮迁移分化成的黑色素细胞TGFβ表达增强、Collagen I/III的表达量随UVB照射强度的增强而增加。同强度UVB照射下，加入RAS、PI3K抑制剂可有效抑制成纤维细胞的活化与增殖，同时下调TGFβ、Collagen I/III的蛋白表达水平。2. α-Mangostin具有降低MITF表达的活性，该活性受RXR和RAR的调控，并可能抑制RAR/RXR异二聚体的形成，从而控制MITF的表达。.科学意义：本研究通过研究黑色素细胞通过影响成纤维细胞参与病理性瘢痕形成的机制，以及α-Mangostin对色素沉着的病理性瘢痕的脱色机制，为瘢痕色素沉着及病理性瘢痕的治疗提供新思路。

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