Therapeutic efficacy of human endometrial stem cells (hEnSCs) encapsulated in hyaluronic acid (HA)-based microcapsules for cardiac regeneration in a rat model of MI is investigated. Cell-enclosed microcapsules were made by loading hEnSCs within hydrogel membrane produced from modified HA possessing phenolic hydroxyl moieties (HA-Ph). The hEnSC-loaded HA-Ph microcapsules (≈150 μm) injected intramyocardially into the peri-infarct area post-MI. The encapsulated cells showed mechanical stability and >
87 % cell viability with cellular aggregation in size of about 100 μm until 7 days of culture. Transthoracic echocardiography evaluation indicated a significant increase in ejection fraction in encapsulated cells, compared to the other groups. Histological investigation of fibrosis and scar area by Masson trichrome and hematoxylin and eosin (H&E) staining illustrated less fibrosis and scarring area in the encapsulated cell group compared with the other groups. Furthermore, the cell-laden microcapsules significantly enhance expression intensities of actin and troponin as well as vascular endothelial-specific marker, all of which promote cardiac functions and contribute to a better therapeutic effect than the free-cell injection group in a rat model of MI. Our findings demonstrated that both hEnSCs and specifically hEnSC-loaded HA-based hydrogel vehicle can provide a promising novel therapy for functional restoration in MI instances.