Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 236, Issue 5, Pages 3991-4007Publisher
WILEY
DOI: 10.1002/jcp.30138
Keywords
Cell modulation; Enthesis; Hedgehog signaling; Hypoxia‐ inducible factors; Osteogenic supplementation
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Funding
- European Union Framework Programme for Research and Innovation HORIZON2020, under the TEAMING Grant [739572]
- ERC Grant CoG MagTendon [772817]
- FCT-Fundacao para a Ciencia e a Tecnologia [PD/BD/128088/2016]
- Fundação para a Ciência e a Tecnologia [PD/BD/128088/2016] Funding Source: FCT
- European Research Council (ERC) [772817] Funding Source: European Research Council (ERC)
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The study investigated the influence of hypoxia and osteogenic medium on cell phenotype modulation using an enthesis coculture model. It was found that hypoxia and osteoinduction promoted a temporal chondro/osteogenic pathway activation, and the presence of OM under hypoxia influenced the extracellular ROS/HIF1A interplay. This research revealed a link between biochemical factors and cell-cell crosstalk towards enthesis-like phenotypes.
Musculoskeletal interfaces are naturally hypoxic. An understanding of key interactions occurring between different cell populations and their environment is critical for native tissue recapitulation. Here, an enthesis coculture model (preosteoblasts and tendon cells) was used to understand the influence of hypoxia (5% O-2) and osteogenic medium (OM) supplementation in cells' phenotype modulation. In single cultures, preosteoblasts were found to undergo osteogenic impairment, while tendon cells underwent a maturation process through extracellular matrix (ECM) rescue. When in co-culture, hypoxia and osteoinduction promoted a temporal chondro/osteogenic pathway activation, as observed by an early deposition of cartilaginous ECM associated with HIF1A stabilization and RUNX2 activation, and later hypertrophic differentiation resulting from HIF2A translocation and SOX9 activation. Moreover, the presence of OM under hypoxia was shown to influence the extracellular ROS/HIF1A interplay. Overall, this study revealed a link between biochemical factors and cell-cell crosstalk, providing a molecular framework for hypoxic control and modulation of cells' fate toward enthesis-like phenotypes.
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