Hypoxia Inducible Factor-1α Deficiency Affects Chondrogenesis of Adipose-Derived Adult Stromal Cells

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Abstract
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-α (HIF-1α), 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-1α in chondrogenesis. Targeted deletion of HIF-1α in ADAS substantially inhibited the chondrogenic pathway specifically. In marked contrast, deletion of HIF-1α did not affect osteogenic differentiation but enhanced adipogenic differentiation. This study demonstrates the critical and specific interplay between HIF-1α and chondrogenesis in vitro.