Graphene Potentiates the Myocardial Repair Efficacy of Mesenchymal Stem Cells by Stimulating the Expression of Angiogenic Growth Factors and Gap Junction Protein

Abstract

Stem cell therapy has emerged as a potential modality for myocardial infarction treatment. Mesenchymal stem cells (MSCs) exert reparative actions in the injured myocardium mainly through the secretion of paracrine factors. In addition, the overexpression of connexin 43 (Cx43), a gap junction protein, promotes cardiac repair and function restoration. It is known that MSCs in a spheroid form, which have enhanced cell-cell interaction, exhibit enhanced expression of paracrine factors and Cx43. However, cell-extracellular matrix (ECM) interactions, which also contribute to growth factor expression, are very limited in MSC spheroids. Reduced graphene oxide (RGO) shows high affi nity toward ECM proteins, such as fi bronectin (FN), and high electrical conductivity. In this study, by incorporating FN-adsorbed RGO fl akes into MSC spheroids, it is possible to enhance the cell-ECM interactions and, subsequently, the paracrine factor expression in the MSCs in spheroids. Cx43 is also upregulated likely due to the enhanced paracrine factor expression and electrical conductivity of RGO. The injection of MSC-RGO hybrid spheroids into the infarcted hearts enhances cardiac repair compared with the injection of RGO fl akes or MSC spheroids. This study demonstrates that RGO can effectively improve the therapeutic effi cacy of MSCs for ischemic heart diseases.

Graphene-based materials for tissue engineering

“…3 (a)) [95]. Incorporation of rGO flakes within hMSC spheroids was shown to alter the expression of cell signaling molecules and improve the expression of cardiac specific markers [96]. The enhanced behavior of cardiac spheroids might be due to the high affinity of rGO flakes towards fibronectin along with high conductivity.…”

Graphene Oxide Hierarchical Patterns for the Derivation of Electrophysiologically Functional Neuron-like Cells from Human Neural Stem Cells

“…[11][12][13] Stem cell engineering using the graphene or chemically exfoliated graphene oxide (GO) has been investigated as one such potential biomedical application, due to its physicochemical and electrical properties that allow control of cellular behaviors (e.g., adhesion, proliferation, differentiation, polarization, and paracrine secretion) and biocompatibility. [14][15][16][17][18] Previous studies have reported enhanced adhesion, proliferation, and differentiation of mesenchymal stem cells on graphene or GO substrates based on their chemical properties and their patterning. 12,19 In addition, it has been demonstrated that the differentiation of neural stem cells (NSCs), which are sensitive to electrical signal, could be promoted on the surface of graphene or GO substrates due to their electrical properties.…”

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

“…GO sheets and flakes with a thickness on the nanometer scale and length in the area of 1-6 μm are not taken up by cells but can absorb ECM proteins from culture serum . Studies by Park et al demonstrated the benefit of incorporating GO or reduced GO flakes into MSC culture, with the following observations: (1) GO adsorbed ECM components (fibronectin) from the serum and formed GO-cell and cell-ECM interactions, which activate both pro-survival pathways and pro-angiogenic cytokine secretion and (2) the conductivity of GO stimulated expression of cardiac specific makers and gap junctions (Park et al, 2015b). The result in vivo in a rodent MI model showed enhanced retention of the MSC + GO in the infarct, reduced sensitivity to oxidative stress following ischemia reperfusion injury, and improvement of heart function by cellular cardiomyoplasty without an immune response to the GO material (Park et al, 2015a).…”

“…Graphene oxide (GO) sheets are an alternative carbon-based nanomaterial, which have shown biocompatibility with no acute toxic effects in vivo (Paul et al, 2014;Park et al, 2015b). GO sheets and flakes with a thickness on the nanometer scale and length in the area of 1-6 μm are not taken up by cells but can absorb ECM proteins from culture serum .…”

“…(i) metal oxide nanoparticles, including reduced graphene oxide (RGO) flakes have antioxtdant properties to protect stem cells [e.g., mesenchymal stem cells (MSCs)] delivered to the infarcted myocardium from reactive oxygen species (ROS). In addition, nanoparticles can prime stem cells to improve therapeutic efficacy [modified with permission from Park et al (2015b))]. (ii) Peptide nanotiber (NF) scaffolds, including RAD16-II hydrogels form microenvironments that can recruit endogenous stem cells or protect exogenous transplanted cells to improve cardiac repair post-injury.…”