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Objective: Cardiosphere-derived cells (CDCs) improve cardiac function and attenuate remodeling in ischemic and non-ischemic cardiomyopathy, and are currently obtained through myocardial biopsy. However, there is not any study on whether functional CDCs may be obtained through cadaveric autopsy with similar benefits in non-ischemic cardiomyopathy. Methods: Cardiac tissues from human or mouse cadavers were harvested, plated at 4°C, and removed at varying time points to culture human CDCs (CLH-EDCs) and mouse CDCs (CM-CDCs). The differentiation and paracrine effects of CDCs were also assessed. Furthermore, intramyocardial injection of cadaveric CM-CDCs was performed in an induced dilated cardiomyopathy (DCM) model. Results: With the extension of post mortem hours, the number of CLH-EDCs and CM-CDCs harvested from autopsy specimens decreased. The expressions of von Willebrand factor (VWF) and smooth muscle actin (SMA) on CDCs were gradually reduced, however, cardiac troponin I (TNI) expression increased in the 24 h group compared to the 0 h group. CLH-EDCs were also found to have similar paracrine function in the 24 h group compared to 0 h group. 8 weeks after CM-CDCs transplantion to the injured heart, mean left ventricular ejection fraction increased in both 0 h (64.99 ± 3.4%) and 24 h (62.99 ± 2.8%) CM-CDCs-treated groups as compared to the PBS treated group (53.64 ± 5.6 cm), with a decrease in left ventricular internal diastolic diameter (0.29 ± 0.08 cm and 0.32 ± 0.04 cm in 0 h and 24 h groups, vs. 0.41 ± 0.05 cm in PBS group). Conclusion: CDCs from cadaveric autopsy are highly proliferative and differentiative, and may be used as a source for allograft transplantation, in order to decrease myocardial fibrosis, attenuate left ventricular remodeling, and improve heart function in doxorubicin-induced non-ischemic cardiomyopathy.

Background In this study, we investig1ated whether microRNA let-7i regulates dendric cell maturation targeting interleukin-10 (IL-10) via the Janus kinase 1–signal transducer and activator of transcription 3 (JAK1-STAT3) signal pathway subsequently prolongs rat cardiac allograft survival. Methods Quantitative real-time reverse transcriptase polymerase chain reaction, enzyme linked immunosorbent assay, and dual-luciferase assay were performed to verify whether IL-10 was the target of let-7i, and regulatory T cells were assessed by flow cytometry and immunohistochemical study. Western blot was performed to detect JAK1, STAT3, and phosphorylated STAT3 expression. Lewis recipients of Dark Agouti hearts were transfused with phosphate-buffered saline, lipopolysaccharide (LPS)-mature dendritic cells (mDCs), or let-7i–inhibitor-mDCs. Allograft survival times were recorded, and histologic studies were performed. Results Expression of IL-10 messenger RNA level and production of IL-10 were increased in let-7i–inhibitor-mDCs compared with LPS-mDCs. Luciferase activity showed that the translational level of the IL-10 luciferase reporter was decreased by let-7i mimic but increased by let-7i-inhibitor. MicroRNA let-7i inhibitor suppressed DC maturation; however, pretreatment of IL-10 small interfering RNA attenuated the suppression. Expression of JAK1, STAT3, and phosphorylated STAT3 in mDCs were suppressed by let-7i mimic, and pre-treatment of IL-10 small interfering RNA, however, were upregulated by let-7i inhibitor. Lewis recipients transfused with let-7i–inhibitor-mDCs significantly prolonged Dark Agouti cardiac allograft survival. The allografts transfused with let-7i–inhibitor-mDCs showed slight cell infiltration and significantly preserved graft structure. Inhibition of let-7i increased CD4 + CD25 + forkhead box P3 + regulatory T cells and modulated cytokine profiles in vivo and in vitro. Conclusions MicroRNA let-7i regulated DC maturation and function targeting IL-10 through the JAK1-STAT3 pathway. Moreover, transfusion of LPS-induced mDCs transfected with let-7i inhibitor induced prolonged cardiac allograft survival and generated regulatory T cells.