Abstract
Adult stem cells can differentiate into multiple lineages depending on their exposure to differing biochemical and biomechanical inductive factors. Lack of mechanical signals due to disuse can inhibit osteogenesis and induce adipogenesis of mesenchymal stem cells (MSCs). Long-term bed rest due to both brain/spinal cord injury and space travel can lead to disuse osteoporosis that is in part caused by a reduced number of osteoblasts. Thus, it is essential to provide proper mechanical stimulation for cellular viability and osteogenesis, particularly under disuse conditions. The objective of this study was to examine the effects of low intensity pulsed ultrasound (LIPUS) on the osteogenic differentiation of adipose-derived human stem cells (Ad-hMSC) in simulated microgravity conditions. Cells were cultured in a 1D clinostat to simulate microgravity (SMG) and treated with LIPUS at 30mW/cm2 for 20 min/day. It was hypothesized that the application of LIPUS to SMG cultures would restore osteogenesis in Ad-hMSCs. The results showed significant increases in ALP, OSX, RANKL, RUNX2, and decreases in OPG in LIPUS treated SMG cultures of Ad-MSC compared to non-treated cultures. LIPUS also restored OSX, RUNX2 and RANKL expression in osteoblast cells. SMG significantly reduced ALP positive cells by 70% (p<0.01) and ALP activity by 22% (p<0.01), while LIPUS treatment restored ALP positive cell number and activity to equivalence with normal gravity controls. Extracellular matrix collagen and mineralization was assessed by Sirius red and Alizarin red staining, respectively. SMG cultures showed little or no collagen or mineralization, but LIPUS treatment restored collagen content to 50% (p<0.001) and mineralization by 45% (p<0.001) in LIPUS treated-SMG cultures relative to SMG-only cultures. The data suggest that LIPUS treatment can restore normal osteogenic differentiation of MSCs from disuse by daily short duration stimulation.
Highlights
Adult mesenchymal stem cells (MSCs) are multi-potent stem cells capable of self-renewal and differentiation into osteoblastic, adipogenic, myogenic, and chondrogenic lineages
Yamazaki et al showed that a lack of mechanical stress can inhibit osteogenesis and induce adipogenesis in bone marrow MSCs [8]
The study was designed to evaluate the effects of low intensity pulsed ultrasound (LIPUS) as a potential countermeasure to MG induced inhibition of osteogenic differentiation of MSCs
Summary
Adult mesenchymal stem cells (MSCs) are multi-potent stem cells capable of self-renewal and differentiation into osteoblastic, adipogenic, myogenic, and chondrogenic lineages. Recent studies have examined the effects of the presence or absence of mechanical stimuli on commitment of MSCs to different lineages [1,2,3]. Luu et al have shown that low magnitude mechanical stimulation (LMMS) induces osteogenesis and inhibit adipogenesis [5,6]. MSCs extracted from LMMS treated mice showed increased expression of RUNX2 relative to PPARγ [5]. A recent study by Yang et al has shown that cyclic tensile strain increased RUNX2 expression while inhibiting PPARγ in rat MSCs [7]. Lack of mechanical stress can induce adipogenesis and inhibit osteogenesis [8,9]. The lack of mechanical stress during spaceflight induces bone loss of
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