Sfrp4蛋白通过调控Wnt/Notch信号轴促进Ctsk+骨外膜干细胞骨修复的机制研究

骨组织工程技术是大段骨缺损修复的有效方法，探寻具有高效成骨性能的种子细胞成为提高其疗效的重要研究方向。组织蛋白酶K阳性骨外膜干细胞（Ctsk+ PSCs）是新近被发现存在于骨外膜的一群干细胞，增值、分化迅速。我们的预实验结果提示Ctsk+ PSCs骨修复能力强，有望作为种子细胞应用于骨修复，且分泌型卷曲蛋白4(Sfrp4)与其成骨分化密切相关。通过构建转基因鼠、测序及细胞实验，我们发现Wnt及Notch通路参与了Sfrp4蛋白调控Ctsk+ PSCs成骨分化的过程，且二者之间可能具有上下游作用关系。据此我们提出假说：Sfrp4蛋白通过介导Wnt/Notch信号轴的交互作用，上调了Ctsk+ PSCs的成骨分化能力，最终促进骨缺损修复。本研究拟在分子、细胞、动物整体水平阐明Sfrp4调控Ctsk+ PSCs促进骨缺损修复的作用及其分子机制。项目的成功实施将为骨缺损修复提供崭新的思路。

Bone tissue engineering technology is an effective method for repairing critical-sized bone defects, and seeking out a kind of high osteogenic potential seed cells is an important task for enhancing the bone regenerative effect. Ctsk+ periosteal stem cells are identified recently as distinct stem cell populations existing in the periosteum. Because of the strong proliferation ability and bone formation capacity, Ctsk+ periosteal stem cells are considered as promising seed cells for bone regeneration tissue engineering. Our preliminary data indicated that Ctsk+ periosteal stem cells had a strong bone regenerative effect. Meanwhile, Secreted frizzled-related protein 4 (Sfrp4) played a central role in the regulation of Ctsk+ periosteal stem cells. We constructed transgenic mice, did RNA sequence and a set of cell experiments. The result suggested that Wnt and Notch signaling pathway were both involved in Sfrp4’s regulation of Ctsk+ periosteal stem cells. And it was possible that there was a up-downstream relationship between these two signaling pathways. Hence we hypothesized that Sfrp4 could enhance the bone regenerative effect of Ctsk+ periosteal stem cells via Wnt/Notch cascade. Our project aims to explore the role of Sfrp4 in Ctsk+ periosteal stem cells during bone defects regeneration. And the successful implementation of this project will produce new breakthroughs in bone regeneration.