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Stem cell-based regenerative therapies are fast becoming an attractive and highly promising treatment for heart disease and failure. Sca-1+/PW1+/Pax7-skeletal muscle-derived interstitial progenitor cells (PICs) regenerate adult skeletal and smooth muscle. Recently, we showed that PICs can differentiate into cardiomyocyte-like cells in vitro. These findings have subsequently opened the potential for PICs to be used as a regenerative therapy in heart failure..We sought to investigate the in-vivo physiological effects of transplantation of PICs in mice subjected to myocardial infarction (MI).Myocardial infarction was induced through the ligation of the left anterior descending coronary artery in 8–9 week old male C57BL/6 mice. 500,000 Sca-1+/PW1+/Pax7- PICs (MI+PICs) or PBS (MI-PBS) were transplanted intramyocardially in two regions of the border zone, immediately after MI induction. SHAM mice underwent the same surgical procedure, without ligating the coronary artery, or the intramyocardial transplantation of PICs or PBS. Echocardiography was performed prior to surgery (baseline), and week 3 post-MI and cell transplantation. Mice were sacrificed at 3 weeks post-MI, and histology and Masson Trichrome staining was performed to assess infarct size and level of fibrosis.A significant (p<0.05) improvement in Ejection Fraction (EF) was observed in MI mice transplanted with PICs (MI-PICs), compared to MI+PBS at week 3 post-MI (55.8±4.2% vs. 35.2±3.6%, respectively). However, this improvement of EF in MI+PICs remained significantly (p<0.05) lower, compared to SHAM (71.1±0.9%) at matched time points, and to corresponding baseline (69.6±0.7%) levels. A similar trend in Fractional Shortening (FS) was observed, where the MI+PICs group showed a significant (p<0.05) improvement, compared to the MI+PBS group (29.2±2.6% vs.17.0±2.0%, respectively). The improvement in FS remained significantly (p<0.05) lower in the MI+PICs group, compared to SHAM (38.8±1.4%) and to corresponding baseline levels (38.8±0.5%). Infarct size and fibrosis significantly (p<0.05) decreased in the MI-PICs group (24.2±2.2% of LV), compared to the MI-PBS group (40.2±2.6% of LV).Transplantation of skeletal muscle-derived Sca-1+/PW1+/Pax7- PICs into the myocardial infarcted myocardium improves cardiac function, and reduces infarct size. Although the mechanism of action needs to be clarified, PICs could be a promising stem/progenitor cell type for the treatment of heart failure.