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Loss of Lgr4 inhibits differentiation,migration and apoptosis,and promotes proliferation in bone mesenchymal stem cells |
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| Authors: | Peng Sun Kunhang Jia Chunbing Zheng Xinlei Zhu Jing Li Liang He Stefan Siwko Feng Xue Mingyao Liu Jian Luo |
| Institution: | 1. Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education, East China Normal University, Shanghai, China Peng Sun and Kunhang Jia contributed equally to this work.;2. Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China Peng Sun and Kunhang Jia contributed equally to this work.;3. Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China;4. Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Department of Orthopaedics, Shanghai Fengxian District Central Hospital, Shanghai, China;5. Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas |
| Abstract: | The key signaling networks regulating bone marrow mesenchymal stem cells (BMSCs) are poorly defined. Lgr4, which belongs to the leucine-rich repeat-containing G protein-coupled receptor (LGR) family, is widely expressed in multiple tissues from early embryogenesis to adulthood. We investigated whether Lgr4 functions in BMSCs and in osteogenesis, adipogenesis, and skeletal myoblasts, using mice with a β-geo gene trap inserted into the Lgr4 gene. Abundant Lgr4 expression was detected in skeletal, adipose and muscular tissue of Lgr4+/– mice at E16.5 by β-gal staining, and Lgr4-deficiency promoted BMSC proliferation (16 ± 4 in wild-type WT] and 28 ± 2 in Lgr4?/?) using colony forming units-fibroblast assay, while suppressing BMSC migration (from 103 ± 18 in WT to 57 ± 10 in Lgr4?/?) by transwell migration assay and apoptosis ratio (from 0.0720 ± 0.0123 to 0.0189 ± 0.0051) by annexin V staining assay. Deletion of Lgr4 decreased bone mass (BV/TV from 19.16 ± 2.14 in WT mice to 10.36 ± 1.96 in KO) and fat mass through inhibiting BMSC differentiation to osteoblasts or adipocytes. Furthermore, LGR4-regulated osteogenic, adipogenic, and myogenic gene expression. Importantly, our data showed that loss of Lgr4-inhibited fracture healing by suppressing osteoblast differentiation. Moreover, deletion of Lgr4 in BMSCs-delayed fracture healing following stem cell therapy by BMSC transplantation. Together, our results demonstrated that LGR4 is essential for mesoderm-derived tissue development and BMSC differentiation, demonstrating that LGR4 could be a promising drug target for related diseases and a critical protein for stem cell therapy. |
| Keywords: | adipogenesis BMSC Lgr4 myoblast osteogenesis |