Malladi Preeti, Xu Yue, Chiou Michael, Giaccia Amato J, Longaker Michael T
Children's Surgical Research Program, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
Tissue Eng. 2007 Jun;13(6):1159-71. doi: 10.1089/ten.2006.0265.
Increased cartilage-related disease, poor regeneration of cartilage tissue, and limited treatment options have led to intense research in tissue engineering of cartilage. Adipose-derived adult stromal cells (ADAS) are a promising cell source for skeletal tissue engineering; understanding ADAS cellular signaling and chondrogenesis will advance cell-based therapies in cartilage repair. Chondrocytes are unique-they are continuously challenged by a hypoxic microenvironment. Hypoxia inducible factor-1-alpha (HIF-1alpha), a critical mediator of a cell's response to hypoxia, plays a significant role in chondrocyte survival, growth arrest, and differentiation. By using an established in vitro 3-dimensional micromass system, we investigated the role of HIF-1alpha in chondrogenesis. Targeted deletion of HIF-1alpha in ADAS substantially inhibited the chondrogenic pathway specifically. In marked contrast, deletion of HIF-1alpha did not affect osteogenic differentiation but enhanced adipogenic differentiation. This study demonstrates the critical and specific interplay between HIF-1alpha and chondrogenesis in vitro.
软骨相关疾病的增加、软骨组织再生能力差以及治疗选择有限，引发了对软骨组织工程的深入研究。脂肪来源的成体基质细胞（ADAS）是骨骼组织工程中一种很有前景的细胞来源；了解ADAS细胞信号传导和软骨形成将推动基于细胞的软骨修复治疗。软骨细胞很独特——它们不断受到低氧微环境的挑战。缺氧诱导因子-1-α（HIF-1α）是细胞对缺氧反应的关键介质，在软骨细胞存活、生长停滞和分化中起重要作用。通过使用已建立的体外三维微团系统，我们研究了HIF-1α在软骨形成中的作用。在ADAS中靶向缺失HIF-1α会特异性地显著抑制软骨形成途径。与之形成鲜明对比的是，缺失HIF-1α并不影响成骨分化，但增强了脂肪生成分化。这项研究证明了体外HIF-1α与软骨形成之间关键且特定的相互作用。
