HIF-1α as a Regulator of BMP2-Induced Chondrogenic Differentiation, Osteogenic Differentiation, and Endochondral Ossification in Stem Cells
HIF-1α as a Regulator of BMP2-Induced Chondrogenic Differentiation, Osteogenic Differentiation, and Endochondral Ossification in Stem Cells
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DOI：
10.1159/000374052
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发表时间：
2015-01-01
影响因子：
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通讯作者：
Huang, Wei
中科院分区：
文献类型：
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作者：
Zhou, Nian;Hu, Ning;Huang, Wei
背景/目的：关节软骨损伤因其自身修复能力有限而难以治疗。基于干细胞和基因增强的软骨组织工程是一种潜在的软骨修复方法。骨形态发生蛋白2(BMP2)可诱导间充质干细胞(MSCs)向软骨细胞分化，但在软骨修复过程中维持MSCs的表型，因为分化是沿着软骨内成骨途径进行的。在这项研究中，低氧诱导因子，或(HIF)-1α，被确定为BMP2诱导的软骨分化、成骨分化和软骨内骨形成的调节因子。方法：用BMP2诱导干细胞向软骨和成骨方向分化，并诱导胎儿肢体发育。在向诱导系统中加入HIF-1α后，评估分化标志物的任何变化。结果：在体外，HIF-1α通过下游标志物增强BMP2诱导的Sox9和软骨形成的表达，通过下游标志物抑制Runx2和成骨的表达。在皮下干细胞植入研究中，HIF-1α被证明能促进BMP2诱导的软骨形成，并抑制异位骨/软骨形成过程中的软骨内成骨。在胎肢培养中，HIF-1α和BMP2协同促进软骨细胞增殖带的扩张，抑制软骨细胞肥大和软骨内成骨。结论：HIF-1α联合BMP2诱导MSC分化可成为软骨组织工程中维持软骨表型的一种新方法。版权所有(C)2015年S.Karger AG，巴塞尔
Background/Aims: Joint cartilage defects are difficult to treat due to the limited self-repair capacities of cartilage. Cartilage tissue engineering based on stem cells and gene enhancement is a potential alternative for cartilage repair. Bone morphogenetic protein 2 (BMP2) has been shown to induce chondrogenic differentiation in mesenchymal stem cells (MSCs); however, maintaining the phenotypes of MSCs during cartilage repair since differentiation occurs along the endochondral ossification pathway. In this study, hypoxia inducible factor, or (HIF)-1 alpha, was determined to be a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral bone formation. Methods: BMP2 was used to induce chondrogenic and osteogenic differentiation in stem cells and fetal limb development. After HIF-1 alpha was added to the inducing system, any changes in the differentiation markers were assessed. Results: HIF-1 alpha was found to potentiate BMP2-induced Sox9 and the expression of chondrogenesis by downstream markers, and inhibit Runx2 and the expression of osteogenesis by downstream markers in vitro. In subcutaneous stem cell implantation studies, HIF-1 alpha was shown to potentiate BMP2-induced cartilage formation and inhibit endochondral ossification during ectopic bone/cartilage formation. In the fetal limb culture, HIF-1 alpha and BMP2 synergistically promoted the expansion of the proliferating chondrocyte zone and inhibited chondrocyte hypertrophy and endochondral ossification. Conclusion: The results of this study indicated that, when combined with BMP2, HIF-1 alpha induced MSC differentiation could become a new method of maintaining cartilage phenotypes during cartilage tissue engineering. Copyright (C) 2015 S. Karger AG, Basel