Mesenchymal stem cell (MSC) implantation has emerged as a potential therapy for myocardial infarction (MI). However, the poor survival of MSCs implanted to treat MI has significantly limited the therapeutic efficacy of this approach. This poor survival is primarily due to reactive oxygen species (ROS) generated in the ischemic myocardium after the restoration of blood flow. ROS primarily causes the death of implanted MSCs by inhibiting the adhesion of the MSCs to extracellular matrices at the lesion site (i.e., anoikis). In this study, we proposed the use of graphene oxide (GO) flakes to protect the implanted MSCs from ROS-mediated death and thereby improve the therapeutic efficacy of the MSCs. GO can adsorb extracellular matrix (ECM) proteins. The survival of MSCs, which had adhered to ECM protein-adsorbed GO flakes and were subsequently exposed to ROS in vitro or implanted into the ischemia-damaged and reperfused myocardium, significantly exceeded that of unmodified MSCs. Furthermore, the MSC engraftment improved by the adhesion of MSCs to GO flakes prior to implantation enhanced the paracrine secretion from the MSCs following MSC implantation, which in turn promoted cardiac tissue repair and cardiac function restoration. This study demonstrates that GO can effectively improve the engraftment and therapeutic efficacy of MSCs used to repair the injury of ROS-abundant ischemia and reperfusion by protecting implanted cells from anoikis.

A simple method that uses graphene to fabricate nanotopographic substrata was reported for stem cell engineering. Graphene-incorporated chitosan substrata promoted adhesion and differentiation of human mesenchymal stem cells (hMSCs). In addition, we proposed that nanotopographic cues of the substrata could enhance cell-cell and cell-material interactions for promoting functions of hMSCs.

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.

The potential of graphene as a mesenchymal stem cell (MSC) culture substrate to promote cardiomyogenic differentiation is demonstrated. Graphene exhibits no sign of cytotoxicity for stem cell culture. MSCs are committed toward cardiomyogenic lineage by simply culturing them on graphene. This may be attributed, at least partially, to the regulation of expression levels of extracellular matrix and signaling molecules.

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