MIF Plays a Key Role in Regulating Tissue-Specific Chondro-Osteogenic Differentiation Fate of Human Cartilage Endplate Stem Cells under Hypoxia
Yao Y, Deng Q, Song W, Zhang H, Li Y, Yang Y, Fan X, Liu M, Shang J, Sun C, Tang Y, Jin X, Liu H, Huang B, Zhou Y.
Degenerative cartilageendplate (CEP) shows decreased chondrification and increased ossification. Cartilageendplatestemcells (CESCs), with the capacity for chondro-osteogenicdifferentiation, are responsible for CEP restoration. CEP is avascular and hypoxic, while the physiological hypoxia is disrupted in the degenerated CEP. Hypoxia promoted chondrogenesis but inhibited osteogenesis in CESCs. This tissue-specificdifferentiationfate of CESCs in response to hypoxia was physiologically significant with regard to CEP maintaining chondrification and refusing ossification. MIF, a downstream target of HIF1A, is involved in cartilage and bone metabolisms, although little is known about its regulatory role in differentiation. In CESCs, MIFwas identified as a key point through which HIF1A regulated the chondro-osteogenicdifferentiation. Unexpectedly, unlike the traditionally recognized mode, increased nuclear-expressed MIFunderhypoxia was identified to act as a transcriptional regulator by interacting with the promoter of SOX9 and RUNX2. This mode of HIF1A/MIF function may represent a target for CEP degeneration therapy.