title: Change in hepatocyte growth factor concentration promote mesenchymal stem cell-mediated osteogenic regeneration.
abstract: Mesenchymal stem cells (MSCs) play a crucial role in tissue repair by secretion of tissue nutrient factors such as hepatocyte growth factor (HGF). However, studies examining the effects of HGF on the proliferation and differentiation of MSCs used different concentrations of HGF and reported conflicting conclusions. This study aimed to determine the mechanisms by which different concentrations of HGF regulate MSC proliferation and osteogenic differentiation, and validate the mechanism in an animal model of early stage avascular necrosis of femoral head (ANFH). Our results demonstrate that a low concentration of HGF (20 ng/ml) preferentially promotes MSC osteogenic differentiation through increased c-Met expression and phosphorylation, Akt pathway activation, and increased expression of p27, Runx2 and Osterix. In contrast, a high concentration of HGF (100 ng/ml) strongly induced proliferation by inducing strong activation of the ERK1/2 signalling pathway. As validated by animal experiments, high localized expression of HGF achieved by transplantation of HGF transgenic MSCs into ANFH rabbits increased the number of MSCs. Subsequently, 2 weeks after transplantation, HGF levels decreased and MSCs differentiated into osteoblasts and resulted in efficient tissue repair. Our results demonstrate that sequential concentration changes in HGF control the proliferation and osteogenic differentiation of MSCs in vivo. This phenomenon can be exploited therapeutically to induce bone regeneration and, in turn, improve the efficacy of pharmacological intervention for ANFH treatment.
authors.affiliation: Institute of Molecular Immunology, School of Biotechnology, Southern Medical University, Guangzhou, China. maryhmz@126.com
authors.forename: Qian
authors.initials: Q
authors.lastname: Wen
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Chaoying
authors.initials: C
authors.lastname: Zhou
authors.forename: Mingqian
authors.initials: M
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Ma
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005271:Femur Head Necrosis / Q000188:drug therapy; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt