Roles of melanocytes in choroid homeostasis

脉络膜是高度血管化的，为视网膜提供氧气和营养。这种色素结缔组织主要由黑色素细胞（色素细胞）、间质成纤维细胞、不同大小的血管以及支持的胶原纤维和弹性纤维组成。对脉络膜黑色素细胞的生物学和功能知之甚少。我的研究项目将利用含黑素细胞、成纤维细胞和内皮细胞的人脉络膜三维组织模型，研究它们在稳态下的细胞间合作，以及衰老过程中微环境因素对脉络膜黑素细胞旁分泌信号和表观基因组的影响。远处的细胞可以通过充满生物活性分子的小口袋（称为细胞外囊泡）发送信号来交换信息。我们最近确定脉络膜黑色素细胞释放细胞外囊泡。此外，表观遗传机制，如DNA羟甲基化，在细胞分化中发挥积极作用。我们最近证实，脉络膜黑色素细胞在其基因组中表现出高DNA羟甲基化含量。我的假设是黑素细胞通过囊外信号在脉络膜血管生成中发挥作用，DNA羟甲基化参与了黑素细胞的分化。因此，我们将确定黑色素细胞胞外囊泡中包含的血管生成因子及其对内皮细胞的作用。我们还将研究DNA羟甲基化分布在调节脉络膜黑色素形成的基因。我的研究项目还将确定与年龄相关的微环境因素，如氧化应激和基质硬化对脉络膜黑素细胞生理的影响。这个研究项目将提高我们对脉络膜中黑素细胞功能的认识。这也将有助于提高我们对微环境因素对细胞外囊泡生物发生和表观遗传修饰的影响的一般认识。

The choroid is highly vascularized and supplies oxygen and nutrients to the retina. This pigmented connective tissue is mainly composed of melanocytes (pigmented cells), stromal fibroblasts, blood vessels of various sizes, and supporting collagenous and elastic fibers. Little is known about the biology and functions of choroidal melanocytes. My research program will use 3-dimensional tissue models of human choroid containing melanocytes, fibroblasts and endothelial cells to study their intercellular cooperation at homeostasis, as well as the impact of microenvironmental factors on the paracrine signaling and epigenome of choroidal melanocytes during aging. Distant cells can exchange information by sending out signals via pockets filled with bioactive molecules called extracellular vesicles. We recently determined that choroidal melanocytes release extracellular vesicles. In addition, epigenetic mechanisms, such as DNA hydroxymethylation, play an active role in cell differentiation. We recently confirmed that choroidal melanocytes exhibit high DNA hydroxymethylation content in their genome. My hypothesis is that melanocytes play a role in choroidal angiogenesis through extravesicular signaling, and that DNA hydroxymethylation is involved in melanocytic differentiation. We will thus determine the angiogenic factors contained in melanocytic extracellular vesicles, and their action on endothelial cells. We will also study the DNA hydroxymethylation distribution in genes that regulate choroidal melanogenesis. My research program will as well determine the impact of age-related microenvironmental factors such as oxidative stress and matrix stiffening on the physiology of choroidal melanocytes. This research program will improve our understanding of the function of melanocytes in the choroid. It will also be very useful for advancing our general knowledge about the impact of microenvironmental factors on extracellular vesicle biogenesis and epigenetic modifications.