ECTS2013 Poster Presentations Chondrocytes and cartilage (20 abstracts)
Oxygen tension-mediated regulation of chondrogenic differentiation: application to stem cells based osteochondral repair
Sophie Portron 1, , Vincent Hivernaud 1, , Christophe Merceron 1, , Julie Lesoeur 1, , Martial Masson 1, , Olivier Gauthier 1, , Claire Vinatier 1, , Laurent Beck 1, & Jerome Guicheux 1,
1INSERM, UMRS 791, Center for Osteoarticular and Dental Tissue Engineering, Group STEP ‘Skeletal Tissue Engineering and Physiopathology’, Nantes, France; 2University of Nantes, UFR Odontology, Nantes, France; 3Center for Preclinical Research and Investigation of the ONIRIS Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering (CRIP), Nantes, France.
Purpose: Multipotent stromal cells (MSC) have been considered promising for the regenerative strategies of articular cartilage. However, the MSC chondrogenic differentiation can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent this MSC-dependent production of a calcified matrix in articular site, MSC hypertrophic differentiation has to be carefully controlled. Given that articular cartilage is avascular, we questioned whether in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their hypertrophic differentiation.
Materials and methods: Human adipose MSC and ATDC5 murine cells were used. Cells were cultured in normoxia (21% O2) or hypoxia (5% O2). The effects of hypoxia on the hypertrophic differentiation was evaluated by i) the production of GAGs by Alcian Blue Staining, ii) the expressions of hypertrophic differentiation markers (Mmp13, Col10A1, Runx2, and AlpL) by RT-PCR and TaqMan low density array, and iii) the measurement of alkaline phosphatase and MMP13 activities. Cell viability was assessed by cell counting and total protein production. The transcriptional activity of hypoxia inducible factor-1α (HIF-1α) and HIF-2α was evaluated by No-Shift DNA binding assay.
Results: Our data indicate that a 5% O2 promoted the transcriptional activity of HIF-1α and HIF-2α. A 5% O2 decreased the production of a calcified matrix, down-regulated the expression of hypertrophic markers and reduces alkaline phosphatase and MMP13 activities as compared to 21% O2, without affecting cell viability and protein production.
Conclusions: Our data suggest that a 5% O2, in addition of being able to chondrogenically commit MSC, inhibits the hypertrophic differentiation of chondrogenic cells. These results make hypoxia an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering. On the contrary, 21% O2 was found to up regulate the terminal differentiation of chondrogenic cells. These data make normoxia a potent factor useful for bone repair through endochondral strategy.
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