Mesenchymal Stem Cell Osteodifferentiation in Response to Alternating Electric Current

Creecy, Courtney M.; O’Neill, Christine F.; Arulanandam, Bernard P.; Sylvia, V. L.; Navara, Christopher S.; Bizios, Rena

doi:10.1089/ten.tea.2012.0091

Cited by 54 publications

(50 citation statements)

References 15 publications

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“…Prior reports in the literature present similar results with respect to osteogenesis when hMSCs were exposed to electrical stimulus in different culture settings. Two studies using electrical current on bone marrow and adipose MSCs, using collagen gels and culture dishes, respectively, found that osteogenesis increased under high currents and voltages 32, 33 . Although the stimulation conditions far exceed what was used in this study, with some reports utilizing a minimum threshold current for increased osteoblastic activity at 100μA/cm 2 34 , it demonstrates that the combination of an appropriate material with stimulation are necessary for late stage osteogenic markers to activate osteogenic differentiation.…”

Section: Resultsmentioning

confidence: 99%

Directing lineage specification of human mesenchymal stem cells by decoupling electrical stimulation and physical patterning on unmodified graphene

et al. 2016

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The organization and composition of the extracellular matrix (ECM) have been shown to impact the propagation of electrical signals in multiple tissue types. To date, many studies with electroactive biomaterial substrates have relied upon passive electrical stimulation of the ionic media to affect cell behavior. However, development of cell culture systems in which stimulation can be directly applied to the material – thereby isolating the signal to the cell-material interface and cell-cell contracts – would provide a more physiologically-relevant paradigm for investigating how electrical cues modulate lineage-specific stem cell differentiation. In the present study, we have employed unmodified, directly-stimulated, (un)patterned graphene as a cell culture substrate to investigate how extrinsic electrical cycling influences the differentiation of naïve human mesenchymal stem cells (hMSCs) without the bias of exogenous biochemicals. We first demonstrated that cyclic stimulation does not deteriorate the cell culture media or result in cytotoxic pH, which are critical experiments for correct interpretation of changes in cell behavior. We then measured how the expression of osteogenic and neurogenic lineage-specific markers were altered simply by exposure to electrical stimulation and/or physical patterns. Expression of the early osteogenic transcription factor RUNX2 was increased by electrical stimulation on all graphene substrates, but the mature marker osteopontin was only modulated when stimulation was combined with physical patterns. In contrast, the expression of the neurogenic markers MAP2 and β3-tubulin were enhanced in all electrical stimulation conditions, and were less responsive to the presence of patterns. These data indicate that specific combinations of non-biological inputs – material type, electrical stimulation, physical patterns – can regulate hMSC lineage specification. This study represents a substantial step in understanding how the interplay of electrophysical stimuli regulate stem cell behavior and helps to clarify the potential for graphene substrates in tissue engineering applications.

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Section: Resultsmentioning

confidence: 99%

Directing lineage specification of human mesenchymal stem cells by decoupling electrical stimulation and physical patterning on unmodified graphene

et al. 2016

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“…13 Both the Creecy et al 13 and the present study used hMSCs that exhibited specific osteodifferentiation in the presence of select bone morphogenetic proteins (BMP-2 and BMP-6) alone. It should be noted, however, that the Creecy et al study did not optimize the conditions that result in osteodifferentiation of these cells under electric current stimulation.…”

Section: Resultsmentioning

confidence: 81%

“…Collagen type I, a hallmark of the osteoblast phenotype, however, was not used as an indicator of osteodifferentiation in this study because it is expressed by both undifferentiated mesenchymal stem cells and osteoblasts. 13,18 Exposure to low frequency (5 Hz), low current level (5 mA), and short duration (1 h) daily to the alternating electric current for up to 7 days, induced expression of early (specifically, TAZ and Runx-2) and middle (specifically, Osterix) osteodifferentiation genes by hMSCs (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

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Adult Human Mesenchymal Stem Cell Differentiation at the Cell Population and Single-Cell Levels Under Alternating Electric Current

Wechsler

Hermann

Bizios

2016

Tissue Engineering Part C: Methods

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Mesenchymal stem cells, precursors that can differentiate into osteoblasts, chondrocytes, and adipocytes, have tremendous potential for derivation of cells with specific (e.g., osteogenic) phenotypes for tissue engineering and tissue regeneration applications. To date, the predominant strategy to achieve directed differentiation of MSCs into osteoblasts was to recapitulate the normal developmental ontogeny of osteoblasts using growth factors (e.g., bone morphogenetic proteins). In contrast, the effects of biophysical stimuli alone on such outcomes remain, at best, partially understood. This in vitro study examined and optimized the effects of alternating electric current alone on the differentiation of adult human mesenchymal stem cells (hMSCs) at the cell population and single-cell levels. hMSCs, cultured on flat, indium-tin-oxide-coated glass in the absence of supplemented exogenous growth factors were exposed to alternating electric current (5-40 mA, 5-10 Hz frequency, sinusoidal waveform), for 1-24 h daily for up to 21 consecutive days. Compared to results obtained from the respective controls, hMSC populations exposed to the alternating electric current alone (in the absence of exogenous growth factors) expressed genes at various stages of differentiation (specifically, TAZ, Runx-2, Osterix, Osteopontin, and Osteocalcin). Optimal osteogenic differentiation was achieved when hMSCs were exposed to a 10 mA, 10 Hz alternating electric current for 6 h daily for up to 21 days. Exclusive osteodifferentiation was observed since genes for the chondrocyte (Collagen Type II) and adipocyte (FABP-4) lineages were not expressed under all conditions of the biophysical stimulus tested. Single cell mRNAs for 45 genes (indicative of hMSC differentiation) were monitored using Fluidigm Systems. Homogeneous expression of the early osteodifferentiation genes (specifically, TAZ and Runx-2) was observed in hMSCs exposed to the alternating electric current at 7 and 21 days. Heterogeneity for all other genes monitored was observed in hMSCs exposed to alternating electric current and in their respective controls. These results provide the first glimpse of gene expression in differentiating hMSCs at the cell population and single-cell levels and represent novel approaches for stem cell differentiation pertinent to new tissue formation.

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“…12,13 In order to exploit the use of electrical stimuli for bone tissue engineering, implanted materials have to possess both electrical conductivity and biocompatibility. Hence, carbon-based materials such as 3D graphene foams (GFs) could be good candidates for biomedical applications.…”

Section: Introductionmentioning

confidence: 99%

Polymer-Enriched 3D Graphene Foams for Biomedical Applications

Wang

Xiong²,

Zhu

et al. 2015

ACS Appl. Mater. Interfaces

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Graphene foams (GFs) are versatile nanoplatforms for biomedical applications because of their excellent physical, chemical, and mechanical properties. However, the brittleness and inflexibility of pristine GF (pGF) are some of the important factors restricting their widespread application. Here, a chemical-vapor-deposition-assisted method was used to synthesize 3D GFs, which were subsequently spin-coated with polymer to produce polymer-enriched 3D GFs with high conductivity and flexibility. Compared to pGF, both poly(vinylidene fluoride)-enriched GF (PVDF/GF) and polycaprolactone-enriched GF (PCL/GF) scaffolds showed improved flexibility and handleability. Despite the presence of the polymers, the polymer-enriched 3D GF scaffolds retained high levels of electrical conductivity because of the presence of microcracks that allowed for the flow of electrons through the material. In addition, polymer enrichment of GF led to an enhancement in the formation of calcium phosphate (Ca-P) compounds when the scaffolds were exposed to simulated body fluid. Between the two polymers tested, PCL enrichment of GF resulted in a higher in vitro mineralization nucleation rate because the oxygen-containing functional group of PCL had a higher affinity for Ca-P deposition and formation compared to the polar carbon-fluorine (C-F) bond in PVDF. Taken together, our current findings are a stepping stone toward future applications of polymer-enriched 3D GFs in the treatment of bone defects as well as other biomedical applications.

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Mesenchymal Stem Cell Osteodifferentiation in Response to Alternating Electric Current

Cited by 54 publications

References 15 publications

Directing lineage specification of human mesenchymal stem cells by decoupling electrical stimulation and physical patterning on unmodified graphene

Directing lineage specification of human mesenchymal stem cells by decoupling electrical stimulation and physical patterning on unmodified graphene

Adult Human Mesenchymal Stem Cell Differentiation at the Cell Population and Single-Cell Levels Under Alternating Electric Current

Polymer-Enriched 3D Graphene Foams for Biomedical Applications

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