Cross‐talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells |
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Authors: | Xing Liu Jiaqiang Qin Qing Luo Yang Bi Gaohui Zhu Wei Jiang Stephanie H Kim Mi Li Yuxi Su Guoxin Nan Jing Cui Wenwen Zhang Ruidong Li Xiang Chen Yuhan Kong Jiye Zhang Jinhua Wang Mary Rose Rogers Hongyu Zhang Wei Shui Chen Zhao Ning Wang Xi Liang Ningning Wu Yunfeng He Hue H Luu Rex C Haydon Lewis L Shi Tingyu Li Tong‐Chuan He Ming Li |
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Institution: | 1. Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics designated by Chinese Ministry of Education and Chongqing Bureau of Education, Department of Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, , Chongqing, China;2. Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, , Chicago, IL, USA;3. Ministry of Education Key Laboratory of Diagnostic Medicine, Department of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, , Chongqing, China;4. Department of Orthopaedic Surgery, the Affiliated Tangdu Hospital, Fourth Military Medical University, , Xi'an, China;5. School of Laboratory Medicine and the Affiliated Southwest Hospital, Third Military Medical University, , Chongqing, China |
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Abstract: | Mesenchymal stem cells (MSCs) are multipotent progenitors, which give rise to several lineages, including bone, cartilage and fat. Epidermal growth factor (EGF) stimulates cell growth, proliferation and differentiation. EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface and stimulating the intrinsic protein tyrosine kinase activity of its receptor, which initiates a signal transduction cascade causing a variety of biochemical changes within the cell and regulating cell proliferation and differentiation. We have identified BMP9 as one of the most osteogenic BMPs in MSCs. In this study, we investigate if EGF signalling cross‐talks with BMP9 and regulates BMP9‐induced osteogenic differentiation. We find that EGF potentiates BMP9‐induced early and late osteogenic markers of MSCs in vitro, which can be effectively blunted by EGFR inhibitors Gefitinib and Erlotinib or receptor tyrosine kinase inhibitors AG‐1478 and AG‐494 in a dose‐ and time‐dependent manner. Furthermore, EGF significantly augments BMP9‐induced bone formation in the cultured mouse foetal limb explants. In vivo stem cell implantation experiment reveals that exogenous expression of EGF in MSCs can effectively potentiate BMP9‐induced ectopic bone formation, yielding larger and more mature bone masses. Interestingly, we find that, while EGF can induce BMP9 expression in MSCs, EGFR expression is directly up‐regulated by BMP9 through Smad1/5/8 signalling pathway. Thus, the cross‐talk between EGF and BMP9 signalling pathways in MSCs may underline their important roles in regulating osteogenic differentiation. Harnessing the synergy between BMP9 and EGF should be beneficial for enhancing osteogenesis in regenerative medicine. |
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Keywords: | BMP9 signalling osteoblastic differentiation EGF signalling mesenchymal stem cells osteogenic differentiation |
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