Human cardiomyocyte-derived exosomes induce cardiac gene expressions in mesenchymal stromal cells within 3D hyaluronic acid hydrogels and in dose-dependent manner

Accomplishing a reliable lineage-specific differentiation of stem cells is vital in tissue engineering applications, however, this need remained unmet. Extracellular nanovesicles (particularly exosomes) have previously been shown to have this potential owing to their rich biochemical content including proteins, nucleic acids and metabolites. In this work, the potential of human cardiomyocytes-derived exosomes to induce in vitro cardiac gene expressions in human mesenchymal stem cells (hMSCs) was evaluated. Cardiac exosomes (CExo) were integrated with hyaluronic acid (HA) hydrogel, which was functionalized with tyramine (HA-Tyr) to enable the development of 3D (three dimensional), robust and bioactive hybrid cell culture construct through oxidative coupling. In HA-Tyr/CExo 3D hybrid hydrogels, hMSCs exhibited good viability and proliferation behaviours. Real time quantitative polymerase chain reaction (RT-qPCR) results demonstrated that cells incubated within HA-Tyr/CExo expressed early cardiac progenitor cell markers (GATA4, Nkx2.5 and Tbx5), but not cTnT, which is expressed in the late stages of cardiac differentiation and development. The expressions of cardiac genes were remarkably increased with increasing CExo concentration, signifying a dose-dependent induction of hMSCs. This report, to some extent, explains the potential of tissue-specific exosomes to induce lineage-specific differentiation. However, the strategy requires further mechanistic explanations so that it can be utilized in translational medicine. [Image: see text]