Iron Oxide Nanoparticle-Mediated Development of Cellular Gap Junction Crosstalk to Improve Mesenchymal Stem Cells’ Therapeutic Efficacy for Myocardial Infarction

Abstract

Electrophysiological phenotype development and paracrine action of mesenchymal stem cells (MSCs) are the critical factors that determine the therapeutic efficacy of MSCs for myocardial infarction (MI). In such respect, coculture of MSCs with cardiac cells has windowed a platform for cardiac priming of MSCs. Particularly, active gap junctional crosstalk of MSCs with cardiac cells in coculture has been known to play a major role in the MSC modification through coculture. Here, we report that iron oxide nanoparticles (IONPs) significantly augment the expression of connexin 43 (Cx43), a gap junction protein, of cardiomyoblasts (H9C2), which would be critical for gap junctional communication with MSCs in coculture for the generation of therapeutic potential-improved MSCs. MSCs cocultured with IONP-harboring H9C2 (cocultured MSCs: cMSCs) showed active cellular crosstalk with H9C2 and displayed significantly higher levels of electrophysiological cardiac biomarkers and a cardiac repair-favorable paracrine profile, both of which are responsible for MI repair. Accordingly, significantly improved animal survival and heart function were observed upon cMSC injection into rat MI models compared with the injection of unmodified MSCs. The present study highlights an application of IONPs in developing gap junctional crosstalk among the cells and generating cMSCs that exceeds the reparative potentials of conventional MSCs. On the basis of our finding, the potential application of IONPs can be extended in cell biology and stem cell-based therapies.

137 Superparamagnetic Iron Oxide Nanoparticle Targeting of Adipose Tissue-Derived Stem Cells in Diabetes-Associated Erectile Dysfunction

“…Moreover, iron oxide nanoparticle-mediated development of cellular gap junction crosstalk among cells improves the therapeutic efficacy of MSCs in myocardial infarction. 41 The molecular mechanisms of the interaction of SPIONs with stem cell biology should be investigated further. Second, we used 30 min as the magnetic attraction time, which might not be the most suitable duration.…”

Radionuclide-embedded gold nanoparticles for enhanced dendritic cell-based cancer immunotherapy, sensitive and quantitative tracking of dendritic cells with PET and Cerenkov luminescence

“…It is believed that the enhanced antitumor immunity originates from the stimulated immune response of the DCs, mediated by the RIe-AuNPs, which requires more detailed future investigation. [31][32][33] Tracking of DC migration to the draining lymph nodes by PET and CLI The potential efficacy of the RIe-AuNPs as an in vivo imaging agent for DC tracking was evaluated using combined PET/CT and CLI imaging, as well as biodistribution study (see Supplementary Figure S10). DCs labeled with the RIe-AuNPs were s.c. injected into the footpad of mice to track migration of the DCs to the DPLNs.…”

Nano-Engineered Biomaterials for Tissue Regeneration: What Has Been Achieved So Far?

“…In tissue engineering applications, magnetic force has been used to successfully manipulate IONP labeled cells in culture to create 3D tissue arrangements, including 3D small-diameter vascular grafts with three layers of cells containing IONP (endothelial, smooth muscle, and fibroblast cell layers) (Ito et al, 2005;Souza et al, 2010). A novel application of IONP by (Han et al, 2015) was to enhance the cardiac lineage differentiation of mesenchymal stem cells (MSCs) prior to delivery to the infarct region post-MI in an effort to enhance cardiomyocytes regeneration. It was proposed that IONP triggered an intracellular signaling cascade, which enabled gap junctional coupling of IONPcardiomyocytes with MSCs, and further activated cross-talk between cells.…”

“…It was proposed that IONP triggered an intracellular signaling cascade, which enabled gap junctional coupling of IONPcardiomyocytes with MSCs, and further activated cross-talk between cells. In this study, a co-culture system of MSCs with WT,wild type;IV,intravenous;PBS,phosphate buffered saline;H,height;I/R,ischemia reperfusion;LV,left ventricular;LVEF,left ventricular ejection fraction;EF,ejection fraction;FS,fractional shortening;LVIDd,left ventricular internal diameter at end diastole;LVIDs,left ventricular internal diameter at end systole;LVEDD,left ventricular end diastolic diameter;HW/BW,heart weight to body weight ratio;alpha sarcomeric actin;JNK,Cx43,connexin 43;βMHC,myosin heavy chain beta;MLC2a,atrial IONP-cardiomyoblasts was employed and the presence of IONP effectively increased cardiomyocyte (CM) markers, gap junctions, and pro-angiogenic cytokine expression in MSCs (Han et al, 2015). These primed MSCs were easily separated from the IONP-cardiomyoblasts via magnetic-activated cell sorting and had significantly greater therapeutic efficacy in a mouse MI model, in terms of preserved cardiac function, lower fibrosis, infarct scar area, and survival 2 weeks post-MI compared to unprimed MSCs (Han et al, 2015).…”