Abstract
Electrical stimulation (ES) is known to guide the development and regeneration of many tissues. However, although preclinical and clinical studies have demonstrated superior effects of ES on cartilage repair, the effects of ES on chondrogenesis remain elusive. Since mesenchyme stem cells (MSCs) have high therapeutic potential for cartilage regeneration, we investigated the actions of ES during chondrogenesis of MSCs. Herein, we demonstrate for the first time that ES enhances expression levels of chondrogenic markers, such as type II collagen, aggrecan, and Sox9, and decreases type I collagen levels, thereby inducing differentiation of MSCs into hyaline chondrogenic cells without the addition of exogenous growth factors. ES also induced MSC condensation and subsequent chondrogenesis by driving Ca2+/ATP oscillations, which are known to be essential for prechondrogenic condensation. In subsequent experiments, the effects of ES on ATP oscillations and chondrogenesis were dependent on extracellular ATP signaling via P2X4 receptors, and ES induced significant increases in TGF-β1 and BMP2 expression. However, the inhibition of TGF-β signaling blocked ES-driven condensation, whereas the inhibition of BMP signaling did not, indicating that TGF-β signaling but not BMP signaling mediates ES-driven condensation. These findings may contribute to the development of electrotherapeutic strategies for cartilage repair using MSCs.
Highlights
That physical factors regulate cell differentiation and tissue development[17,18,19,20,21], suggesting therapeutic potential of physical factors as alternatives to chemical agents for cartilage regeneration
Because ATP oscillations were driven by changes in Ca2+ concentrations during chondrogenesis[38], we examined Ca2+ oscillations using the bioluminescent Ca2+ reporter Aequorin (AQ) gene fused to a CMV promoter (PCMV-AQ)[44]
These results indicate that electrical stimulation (ES) induces prechondrogenic condensation by driving Ca2+/ATP oscillations, even in the absence of exogenous growth factors
Summary
That physical factors regulate cell differentiation and tissue development[17,18,19,20,21], suggesting therapeutic potential of physical factors as alternatives to chemical agents for cartilage regeneration. The precise roles of ES and EMF in cartilage repair remains unclear, and the effects of ES and EMF have only been observed in the surrounding cartilage, and not in articular defects. These observations indicate that ES or EMF alone have limited therapeutic efficacy for the repair of large osteochondral defects. Recent studies have reported the effects of ES on proliferation and differentiation of MSCs36,37, it remains unclear whether ES induces chondrogenic differentiation of MSCs. Our previous studies demonstrated that intracellular ATP levels oscillate during chondrogenic differentiation and the ATP oscillations play critical roles in prechondrogenic condensation[38,39], and that extracellular ATP signaling mediates the ATP oscillations during chondrogenesis[40]. The present data suggest that ES has high potential as an MSC-based therapy for cartilage regeneration
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