Enhancement of mesenchymal stem cell chondrogenesis with short-term low intensity pulsed electromagnetic fields

Abstract

Pulse electromagnetic fields (PEMFs) have been shown to recruit calcium-signaling cascades common to chondrogenesis. Here we document the effects of specified PEMF parameters over mesenchymal stem cells (MSC) chondrogenic differentiation. MSCs undergoing chondrogenesis are preferentially responsive to an electromagnetic efficacy window defined by field amplitude, duration and frequency of exposure. Contrary to conventional practice of administering prolonged and repetitive exposures to PEMFs, optimal chondrogenic outcome is achieved in response to brief (10 minutes), low intensity (2 mT) exposure to 6 ms bursts of magnetic pulses, at 15 Hz, administered only once at the onset of chondrogenic induction. By contrast, repeated exposures diminished chondrogenic outcome and could be attributed to calcium entry after the initial induction. Transient receptor potential (TRP) channels appear to mediate these aspects of PEMF stimulation, serving as a conduit for extracellular calcium. Preventing calcium entry during the repeated PEMF exposure with the co-administration of EGTA or TRP channel antagonists precluded the inhibition of differentiation. This study highlights the intricacies of calcium homeostasis during early chondrogenesis and the constraints that are placed on PEMF-based therapeutic strategies aimed at promoting MSC chondrogenesis. The demonstrated efficacy of our optimized PEMF regimens has clear clinical implications for future regenerative strategies for cartilage.

Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration

“…This is supported by studies showing PEMF inhibition of the PGE2 and cycloxigenase-2 (COX-2) pathways, reducing the expression of pro-inflammatory cytokines (IL-6, IL-8) while augmenting anti-inflammatory factors (cAMP, IL-10) in synovial fibroblasts from bovine and osteoarthritic patients [42][43][44]. Here, we provide evidence that the previously described pro-chondrogenic of PEMF stimulation [34] can be largely attributed to its modulation of the MSC secretome ( Fig. 1).…”

“…The PEMF device used in this study has been previously described [34,35]. Briefly, the device produces spatially homogeneous, time-varying magnetic fields, consisting of barrages of 20 × 150 μs on and off pulses for 6 ms repeated at a frequency of 15 Hz.…”

“…We have previously shown that pulsed electromagnetic fields (PEMFs) activate calcium-permeable transient receptor potential (TRP) channels, promoting both in vitro chondrogenesis [34] and myogenesis [35] by activating a calcium-mitochondrial transcriptional and epigenetic axes governing survival and development [35]. PEMFinduced MSC differentiation has been correlated with increased expression of TGFβ and BMP2 [36][37][38].…”

Efficacy of pulsed electromagnetic fields and electromagnetic fields tuned to the ion cyclotron resonance frequency of Ca2+on chondrogenic differentiation

“…In another study, the PEMF stimulation (1.8–3 mT, 75 Hz) of cultured chondrocytes on chitosan films led to higher amounts of GAGs and type II collagen deposition (Chang, Hsiao, & Lin, ). On the other hand, an alternative study reported that MSCs' chondrogenic induction is preferentially responsive to a single exposure (2 mT, 15 Hz, 10 min) during the chondrogenesis process (Parate et al, ). The applied frequency is also a critical parameter in PEMF stimulation.…”

“…As mentioned earlier, physical loads affect intracellular Ca 2+ transient, thus the decreased chondrogenic gene expressions in a combined stimulation condition might be due to the same feedback effect as suggested. Furthermore, Parate et al () report a dosage‐dependent (2 mT, 10 min, once on day 1 of chondrogenic induction) effectiveness of PEMF exposure in inducing chondrogenesis in cell pellets cultured in chondrogenic media. They discuss that induction of calcium influx by repeated pulsing at later stages of chondrogenesis is suppressive of MSCs' chondrogenesis and the reduced chondrogenic expression in prolonged/repeated PEMF exposure conditions is not the result of cell death but probably deferred chondrogenesis towards osteogenesis.…”