Human bone marrow-derived stem cell proliferation is inhibited by hepatocyte growth factor via increasing the cell cycle inhibitors p53, p21 and p27
Human bone marrow-derived stem cell proliferation is inhibited by hepatocyte growth factor via increasing the cell cycle inhibitors p53, p21 and p27
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DOI：
10.1016/j.bone.2011.08.023
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发表时间：
2011-12-01
期刊：
影响因子：
4.1
通讯作者：
Howard, Guy A.
中科院分区：
文献类型：
--
作者：
Chen, Ketian;Perez-Stable, Carlos;Howard, Guy A.
人骨髓源性干细胞（hMSCs）是骨祖细胞的主要来源。肝细胞生长因子（HGF）是由hMSCs组成性产生的糖蛋白，据报道其作用于分化的成骨细胞和破骨细胞。而且。我们和其他人已经证明HGF可以增强hMSCs向成骨细胞的分化。通常，HGF的促分化作用需要与调节因子如维生素D或骨基质材料的协同作用。在这里，我们探讨了HGF对hMSC（骨形成细胞的主要前体细胞）成骨作用的分子机制。与对照（未处理）细胞相比，HGF处理的hMSC随着时间的推移减少了细胞数量，并增加了G1/S细胞周期阻滞。RT-qPCR显示HGF处理增加了细胞周期抑制剂p53、p21和p27的基因表达，这可能解释了细胞生长抑制和Cl阻滞，这是表型分化的关键步骤。cMet（HGF受体）特异性siRNA的转染消除了HGF对hMSCs的抗增殖作用以及HGF介导的p53、p21和p27的增加，强烈支持这些细胞周期抑制剂在HGF调节hMSCs中的作用。HGF与已知的成骨分化诱导剂1，25-二羟维生素D组合。细胞成熟/分化显著增加，如几种成骨细胞标志物的增加所示。综上所述，这些结果表明，HGF显着增强hMSC成骨细胞分化的1，25-二羟维生素D。爱思唯尔公司出版
Human bone marrow-derived stem cells (hMSCs) are a major source of osteoprogenitors. Hepatocyte growth factor (HGF), a glycoprotein constitutively produced by hMSCs, is reported to act on differentiated osteoblasts and also osteoclasts. Moreover. HGF has been shown by us and others to enhance osteoblastic differentiation from hMSCs. Typically, the pro-differentiation effects of HGF have required cooperative action with regulatory factors such as vitamin D or bone matrix material. Here, we have pursued the molecular mechanisms underlying the osteogenic effect of HGF on hMSCs, the principal precursors to bone forming cells. HGF treatment of hMSCs reduced the cell number over time and increased G1/S cell-cycle arrest compared to control (non-treated) cells. RT-qPCR showed treatment with HGF increased gene expression of the cell-cycle inhibitors p53, p21, and p27, possibly explaining the cell growth inhibition and Cl arrest, a step critical to phenotypic differentiation. Transfection of siRNA specific for cMet, the HGF receptor, eliminated the HGF anti-proliferation effect on hMSCs and the HGF-mediated increase in p53, p21, and p27, strongly supporting a role for these cell-cycle inhibitors in HGF's regulation of hMSCs. HGF in combination with a known inducer of osteogenic differentiation, 1,25-dihydroxyvitamin D. significantly increased cell maturation/differentiation as indicated by an increase in several osteoblast markers. Taken together these results demonstrate that HGF significantly enhances hMSC osteoblast differentiation by 1,25-dihydroxyvitamin D. Published by Elsevier Inc.