色素上皮衍生因子（PEDF）介导Notch信号通路调控巨噬细胞极化在扩张皮肤中的机制研究

扩张后真皮组织变薄，进而导致扩张效率不佳是皮肤软组织扩张术临床应用亟待解决的问题。成纤维细胞增殖和胶原合成不足是真皮组织变薄的重要原因。课题组前期研究发现：巨噬细胞在维持真皮厚度和胶原合成中起关键作用，并且受扩张皮肤微环境中PEDF调控。研究还发现PEDF通过上调Notch信号通路促使巨噬细胞向M1型极化，并减弱成纤维细胞胶原合成。以上结果提示，扩张皮肤高表达的PEDF经旁分泌途径释放到真皮组织，通过激活巨噬细胞Notch信号通路使其向M1极化，从而减缓成纤维细胞增殖和胶原合成的能力。本课题拟以PEDF为切入点，采用缺氧和牵拉等手段，阐明PEDF通过Notch信号介导巨噬细胞极化的机制；同时利用PEDF基因敲除小鼠和RBP-J基因敲除小鼠，阐述PEDF影响真皮新生的分子机制。本研究旨在从新的角度阐明扩张真皮变薄机制，为临床提高扩张效率、降低扩张并发症提供理论依据。

Dermal tissue thinning after skin expansion results in poor expansion efficiency, which is the key issue need to be solved during the clinical application of skin and soft tissue expansion. Insufficient fibroblasts proliferation and collagen synthesis are important causes of dermal thinning. Our previous study found that macrophages played a necessary role in the proliferation and collagen synthesis of fibroblasts, and macrophages were regulated by PEDF in the expanded microenvironment. Additional in vitro research showed that PEDF determined M1 polarization of macrophages by up-regulating Notch signaling pathway. The above results suggest that PEDF, which is highly expressed in expanded skin, is released into dermal tissue via paracrine pathway and polarized M1 macrophages through the activation of Notch signaling pathway, which impede the ability of fibroblasts proliferation and collagen synthesis. By targeting PEDF, this research plans to use hypoxia and mechanical stretch in vitro to elucidate the molecular mechanism of PEDF-mediated Notch signaling and regulation of macrophages polarization; and PEDF knockout mice and RBP-J knockout mice were used to elucidate the role of PEDF and Notch signaling in skin regeneration during tissue expansion. This study tends to elucidate the mechanism of thinned dermis during skin expansion from a new perspective, and provides theoretical foundation to improve expansion efficiency and reduce complications of tissue expansion.