Wang Nan, Shen Xiaoyu, Huang Huakun, Zhao Runhan, Jiwa Habu, Li Zongxin, Li Pei, Ye Jixing, Zhou Qiang
Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
Key Laboratory of Clinical Laboratory Diagnostics, Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Genes Dis. 2024 May 9;12(4):101317. doi: 10.1016/j.gendis.2024.101317. eCollection 2025 Jul.
Amyloid precursor protein (APP), especially Swedish mutant APP (APPswe), is recognized as a significant pathogenic protein in Alzheimer's disease, but limited research has been conducted on the correlation between APPswe and the osteogenic differentiation of mesenchymal stem cells (MSCs). The effects of APPswe and its intracellular and extracellular segments on the osteogenic differentiation of bone morphogenetic protein 2 (BMP2)-induced MSCs were analyzed in this study. Our analysis of an existing database revealed that APP was positively correlated with the osteogenic differentiation of MSCs but negatively correlated with their proliferation and migration. Furthermore, APPswe promoted BMP2-induced osteogenic differentiation of MSCs, while APPswe-C (APPswe without an intracellular segment) had the opposite effect; thus, the intracellular domain of APPswe may be a key factor in promoting the osteogenic differentiation of MSCs. Additionally, both APPswe and APPswe-C inhibited the proliferation and migration of MSCs. Furthermore, the intracellular domain of APPswe inhibited the activity of the Notch pathway by regulating the expression of the Notch intracellular domain to promote the osteogenic differentiation of MSCs. Finally, APPswe-treated primary rat bone marrow MSCs exhibited the most favorable bone repair effect when a GelMA hydrogel loaded with BMP2 was used for experiments, while APPswe-C had the opposite effect. These findings demonstrate that APPswe promotes the osteogenic differentiation of MSCs by regulating the Notch pathway, but its extracellular segment blocks the self-renewal, proliferation, and migration of MSCs, ultimately leading to a gradual decrease in the storage capacity of MSCs and affecting long-term bone formation.
淀粉样前体蛋白（APP），尤其是瑞典突变型APP（APPswe），被认为是阿尔茨海默病中的一种重要致病蛋白，但关于APPswe与间充质干细胞（MSCs）成骨分化之间的相关性研究较少。本研究分析了APPswe及其细胞内和细胞外片段对骨形态发生蛋白2（BMP2）诱导的MSCs成骨分化的影响。我们对现有数据库的分析表明，APP与MSCs的成骨分化呈正相关，但与它们的增殖和迁移呈负相关。此外，APPswe促进了BMP2诱导的MSCs成骨分化，而APPswe-C（无细胞内片段的APPswe）则有相反的作用；因此，APPswe的细胞内结构域可能是促进MSCs成骨分化的关键因素。此外，APPswe和APPswe-C均抑制了MSCs的增殖和迁移。此外，APPswe的细胞内结构域通过调节Notch细胞内结构域的表达来抑制Notch信号通路的活性，从而促进MSCs的成骨分化。最后，当使用负载有BMP2的GelMA水凝胶进行实验时，经APPswe处理的原代大鼠骨髓MSCs表现出最有利的骨修复效果，而APPswe-C则有相反的效果。这些发现表明，APPswe通过调节Notch信号通路促进MSCs的成骨分化，但其细胞外片段会阻碍MSCs的自我更新、增殖和迁移，最终导致MSCs的储存能力逐渐下降，并影响长期骨形成。
