SummaryDilated cardiomyopathy (DCM), as one of the common cardiomyopathies, is a disease of the heart muscle; however, the etiology and pathogenesis of DCM were still poorly understood. Nestin has been reported a special marker of stem/progenitor cells in various tissues, and the tissue resident Nestin + cells could promote the wound healing and tissue remodeling. However, it remains unclear whether Nestin + cells participate in the protection of cardiomyocytes during the pathogenesis of DCM. Here the model of mice DCM was induced by doxorubicin (DOX) intraperitoneal injection and observed heart failure and ventricular enlargement via echocardiography and histologic analysis, respectively. During DCM pathogenesis, the number of Nestin + cells showed a significant peak on day 6 after DOX treatment, which then gradually decreases to lower than normal levels after day 30 in the total population of the heart. Furthermore, we found that the isolated increased heart-derived Nestin + cells are mesenchymal property and could protect DOX-induced HL-1 cells toxicity in vitro by promoting their proliferation and inhibiting their apoptosis. Collectively, our results showed that Nestin + cells increased during DCM pathogenesis and played an important role in protecting against the DOX-induced HL-1 cells loss via regulating proliferation and apoptosis. Thus, the loss of Nestin + cells might be an etiology to DCM pathogenesis, and these cells could be a promising candidate cell source for study and treatment of DCM patients.(Int Heart J 2018; 59: 180-189)