Mechanical signal influence on mesenchymal stem cell fate is enhanced by incorporation of refractory periods into the loading regimen

Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Journal of Biomechanics (Impact Factor: 2.5). 02/2011; 44(4):593-9. DOI: 10.1016/j.jbiomech.2010.11.022
Source: PubMed

ABSTRACT Mechanical signals of both low and high intensity are inhibitory to fat and anabolic to bone in vivo, and have been shown to directly affect mesenchymal stem cell pools from which fat and bone precursors emerge. To identify an idealized mechanical regimen which can regulate MSC fate, low intensity vibration (LIV; <10 microstrain, 90 Hz) and high magnitude strain (HMS; 20,000 microstrain, 0.17 Hz) were examined in MSC undergoing adipogenesis. Two x twenty minute bouts of either LIV or HMS suppressed adipogenesis when there was at least a 1h refractory period between bouts; this effect was enhanced when the rest period was extended to 3h. Mechanical efficacy to inhibit adipogenesis increased with additional loading bouts if a refractory period was incorporated. Mechanical suppression of adipogenesis with LIV involved inhibition of GSK3β with subsequent activation of β-catenin as has been shown for HMS. These data indicate that mechanical biasing of MSC lineage selection is more dependent on event scheduling than on load magnitude or duration. As such, a full day of rest should not be required to "reset" the mechanical responsiveness of MSCs, and suggests that incorporating several brief mechanical challenges within a 24h period may improve salutary endpoints in vivo. That two diverse mechanical inputs are enhanced by repetition after a refractory period suggests that rapid cellular adaptation can be targeted.

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    ABSTRACT: Osteoporosis can be associated with the disordered balance between osteogenesis and adipogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). Although low-frequency mechanical vibration has been demonstrated to promote osteogenesis, little is known about the influence of acoustic-frequency vibratory stimulation (AFVS). BM-MSCs were subjected to AFVS at frequencies of 0, 30, 400, and 800 Hz and induced toward osteogenic or adipogenic-specific lineage. Extracellular matrix mineralization was determined by Alizarin Red S staining and lipid accumulation was assessed by Oil Red O staining. Transcript levels of osteogenic and adipogenic marker genes were evaluated by real-time reverse transcription-polymerase chain reaction. Cell proliferation of BM-MSCs was promoted following exposure to AFVS at 800 Hz. Vibration at 800 Hz induced the highest level of calcium deposition and significantly increased mRNA expression of COL1A1, ALP, RUNX2, and SPP1. The 800 Hz group downregulated lipid accumulation and levels of adipogenic genes, including FABP4, CEBPA, PPARG, and LEP, while vibration at 30 Hz supported adipogenesis. BM-MSCs showed a frequency-dependent response to acoustic vibration. AFVS at 800 Hz was the most favorable for osteogenic differentiation and simultaneously suppressed adipogenesis. Thus, acoustic vibration could potentially become a novel means to prevent and treat osteoporosis.
    02/2015; 2015:1-10. DOI:10.1155/2015/540731
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    ABSTRACT: Purpose of review The musculoskeletal system is largely regulated through dynamic physical activity and is compromised by cessation of physical loading. There is a need to recreate the anabolic effects of loading on the musculoskeletal system, especially in frail individuals who cannot exercise. Vibration therapy is designed to be a nonpharmacological analogue of physical activity, with an intention to promote bone and muscle strength. Recent findings Animal and human studies suggest that high-frequency, low-magnitude vibration therapy improves bone strength by increasing bone formation and decreasing bone resorption. There is also evidence that vibration therapy is useful in treating sarcopenia, which confounds skeletal fragility and fall risk in aging. Enhancement of skeletal and muscle strength involves regulating the differentiation of mesenchymal stem cells to build these tissues; mesenchymal stem cell lineage allocation is positively promoted by vibration signals. Summary Vibration therapy may be useful as a primary treatment as well as an adjunct to both physical and pharmacological treatments, but future studies must pay close attention to compliance and dosing patterns, and importantly, the vibration signal, be it low-intensity vibration (< 1g) appropriate for treatment of frail individuals or high-intensity vibration (> 1g) marketed as a training exercise.
    Current Opinion in Endocrinology Diabetes and Obesity 12/2014; 21(6):447-53. DOI:10.1097/MED.0000000000000111 · 3.77 Impact Factor
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    ABSTRACT: Variables defining vibration-based biomechanical treatments were tested by their ability to affect the musculoskeleton in the growing mouse. Duration of a vibration bout, but not variations in vibration intensity or number of vibration bouts per day, was identified as modulator of trabecular bone formation rates. Low-intensity vibrations (LIV) may enhance musculoskeletal properties, but little is known regarding the role that individual LIV variables play. We determined whether acceleration magnitude and/or the number and duration of daily loading bouts may modulate LIV efficacy. LIV was applied to 8-week-old mice at either 0.3 g or 0.6 g for three weeks; the number of daily bouts was one, two, or four, and the duration of a single bout was 15, 30, or 60 min. A frequency of 45 Hz was used throughout. LIV induced tibial cortical surface strains in 4-month-old mice of approximately 10 με at 0.3 g and 30 με at 0.6 g. In trabecular bone of the proximal tibial metaphysis, all single daily bout signal combinations with the exception of a single 15 min daily bout at 0.3 g (i.e., single bouts of 30 and 60 min at 0.3 g and 15 and 30 min at 0.6 g) produced greater bone formation rates (BFR/BS) than in controls. Across all signal combinations, 30 and 60 min bouts were significantly more effective than 15 min bouts in raising BFR/BS above control levels. Increasing the number of daily bouts or partitioning a single daily bout into several shorter bouts did not potentiate efficacy and in some instances led to BFR/BS that was not significantly different from those in controls. Bone chemical and muscle properties were similar across all groups. These data may provide a basis towards optimization of LIV efficacy and indicate that in the growing mouse skeleton, increasing bout duration from 15 to 30 or 60 min positively influences BFR/BS.
    Osteoporosis International 01/2015; 26(4). DOI:10.1007/s00198-014-3018-5 · 4.17 Impact Factor

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