Transplantation of adipose-derived stem cells combined with neuregulin-microparticles promotes efficient cardiac repair in a rat myocardial infarction model.

Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-d-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy.

Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window.

Therapies developed for adult patients with heart failure have been shown to be ineffective in pediatric clinical trials, leading to the recognition that new pediatric-specific therapies for heart failure must be developed. Administration of the recombinant growth factor neuregulin-1 (rNRG1) stimulates regeneration of heart muscle cells (cardiomyocytes) in adult mice. Because proliferation-competent cardiomyocytes are more abundant in growing mammals, we hypothesized that administration of rNRG1 during the neonatal period might be more effective than in adulthood. If so, neonatal rNRG1 delivery could be a new therapeutic strategy for treating heart failure in pediatric patients. To evaluate the effectiveness of rNRG1 administration in cardiac regeneration, newborn mice were subjected to cryoinjury, which induced myocardial dysfunction and scar formation and decreased cardiomyocyte cell cycle activity. Early administration of rNRG1 to mice from birth to 34 days of age improved myocardial function and reduced the prevalence of transmural scars. In contrast, administration of rNRG1 from 4 to 34 days of age only transiently improved myocardial function. The mechanisms of early administration involved cardiomyocyte protection (38%) and proliferation (62%). We also assessed the ability of rNRG1 to stimulate cardiomyocyte proliferation in intact cultured myocardium from pediatric patients. rNRG1 induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age. Our results identify an effective time period within which to execute rNRG1 clinical trials in pediatric patients for the stimulation of cardiomyocyte regeneration.

[Effects of recombined human neuregulin on the contractibility of cardiac muscles of rhesus monkeys with pacing-induced heart failure].

OBJECTIVE: To evaluate the effects of recombined human Neuregulin on the contractibility of cardiac muscles of Rhesus Monkeys with pacing-induced heart failure and to reveal the possible mechanisms involved. METHODS: Twenty four rhesus monkeys were randomly divided into three groups (shame operated group, heart failure group and Neuregulin treated group), each with 8 monkeys. Heart failures were induced by rapid pacing (240 heartbeats/min). Daily intravenous injection of recombined human Neuregulin [3 microg/(kg x d)] and medical salt fluid were given to the monkeys for 10 days for the Neuregulin treated group and heart failure group respectively. Hemodynamic measurements such as peak positive rate of change in left ventricular blood pressure (+dP/dtmax) and left ventricular systolic, and end-diastolic blood pressures (LVSP and LVEDP) were compared between groups. The real-time quantitative RT-PCR was undertaken to detect the expression of myosin heavy chain mRNA in the left ventricular cardiac muscle. RESULTS: The monkeys in the heart failure group had lower levels of +dP/dtmax and LVSP and higher levels of LVEDP than those in the shame operated group (P < 0.05). The monkeys in the Neuregulin treated group had higher levels of + dP/dtmax than those in the heart failure group (P < 0.05). Lower expression of alpha-myosin heavy chain mRNA in the heart failure group was found compared with the shame operated group and Neuregulin treated group (P < 0.05). CONCLUSION: Recombined human Neuregulin can enhance the contractibility of cardiac muscles and relieve heart failure syndrome through reversing the falling of alpha-myosin heavy chain induced by rapid ventricular pacing.

Growth factor NUN increased AKR1C2 expression by activated CDK2 related RB signal transduction pathway in human liver cancer cell line.

BACKGROUND/AIMS: The investigation is to understand whether polypeptide growth factor NUN can enhance AKR1C2 transcriptional expression in human SMMC7721 liver cancer cell line or not. METHODOLOGY: SMMC7721 cell was starved in serum-free medium overnight before NUN treatment, and cells were then incubated with NUN for different times and dosage. These cells lysates were prepared to examine AKR1C2 expression by Western blot. Total RNA was extracted from these cells to analyze the change of AKR1C2 mRNA by Northern blot. RESULTS: NUN increased expression of AKR1C2 in SMMC7721 liver cancer cell in a time- and dosage-dependent manner and this increase resulted from up-regulation of AKR1C2 mRNA expression. The inhibitor of CDK2 inhibited the up-regulation of AKR1C2 by NUN. CONCLUSIONS: These results showed that NUN can enhance AKR1C2 transcription by activated CDK2 related RB signaling pathway, leading to increased AKR1C2 expression in SMMC7721 liver cancer cell.