The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling
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 e...
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KeAi Communications Co., Ltd.
2025-07-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304224001144 |
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| author | Nan Wang Xiaoyu Shen Huakun Huang Runhan Zhao Habu Jiwa Zongxin Li Pei Li Jixing Ye Qiang Zhou |
| author_facet | Nan Wang Xiaoyu Shen Huakun Huang Runhan Zhao Habu Jiwa Zongxin Li Pei Li Jixing Ye Qiang Zhou |
| author_sort | Nan Wang |
| collection | DOAJ |
| description | 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 in vivo 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. |
| format | Article |
| id | doaj-art-a1bac68a5df047ee9b6966ad91832ffb |
| institution | Kabale University |
| issn | 2352-3042 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Genes and Diseases |
| spelling | doaj-art-a1bac68a5df047ee9b6966ad91832ffb2025-08-20T03:52:37ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422025-07-0112410131710.1016/j.gendis.2024.101317The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signalingNan Wang0Xiaoyu Shen1Huakun Huang2Runhan Zhao3Habu Jiwa4Zongxin Li5Pei Li6Jixing Ye7Qiang Zhou8Department 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, ChinaChengdu University, Chengdu 610106, ChinaKey Laboratory of Clinical Laboratory Diagnostics, Ministry of Education, Chongqing Medical University, Chongqing 400016, ChinaDepartment of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, ChinaKey Laboratory of Clinical Laboratory Diagnostics, Ministry of Education, Chongqing Medical University, Chongqing 400016, China; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, ChinaDepartment of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, ChinaDepartment of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China; Corresponding author.Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China; Corresponding author.Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China; Corresponding author.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 in vivo 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.http://www.sciencedirect.com/science/article/pii/S2352304224001144Alzheimer's diseaseAmyloid precursor proteinMSCsNotch signalingOsteogenic differentiation |
| spellingShingle | Nan Wang Xiaoyu Shen Huakun Huang Runhan Zhao Habu Jiwa Zongxin Li Pei Li Jixing Ye Qiang Zhou The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling Genes and Diseases Alzheimer's disease Amyloid precursor protein MSCs Notch signaling Osteogenic differentiation |
| title | The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling |
| title_full | The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling |
| title_fullStr | The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling |
| title_full_unstemmed | The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling |
| title_short | The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signaling |
| title_sort | bidirectional effects of appswe on the osteogenic differentiation of mscs in bone homeostasis by regulating notch signaling |
| topic | Alzheimer's disease Amyloid precursor protein MSCs Notch signaling Osteogenic differentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2352304224001144 |
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