Nr2e1 Downregulation Is Involved in Excess Retinoic Acid-induced Developmental Abnormality in the Mouse Brain / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>This study aimed to investigate the expression pattern and function of Nuclear receptor subfamily 2 group E member 1 (Nr2e1) in retinoic acid (RA)-induced brain abnormality.</p><p><b>METHODS</b>The mouse model of brain abnormality was established by administering 28 mg/kg RA, and neural stem cells (NSCs) were isolated from the mouse embryo and cultured in vitro. Nr2e1 expression was detected by whole mount in situ hybridization, RT-PCR, and Western blotting. Nr2e1 function was determined by transducing Nr2e1 shRNA into NSCs, and the effect on the sonic hedgehog (Shh) signaling pathway was assessed in the cells. In addition, the regulation of Nr2e1 expression by RA was also determined in vitro.</p><p><b>RESULTS</b>Nr2e1 expression was significantly downregulated in the brain and NSCs of RA-treated mouse embryos, and knockdown of Nr2e1 affected the proliferation of NSCs in vitro. In addition, a similar expression pattern of Nr2e1 and RA receptor (RAR) α was observed after treatment of NSCs with different concentrations of RA.</p><p><b>CONCLUSION</b>Our study demonstrated that Nr2e1 could be regulated by RA, which would aid a better understanding of the mechanism underlying RA-induced brain abnormality.</p>

Cell Transplantation to Improve Heart Function: Cell or Matrix

Current attempts to regenerate the damaged myocardium after myocardial infarction have primarily focused on therapies directed at increasing regional perfusion and reducing cell loss. Accumulating evidence suggests that implantation of healthy muscle cells into the damaged myocardium replaces the fibrotic tissue. In addition to muscle cells, stem cells in circulation, from bone marrow or in the myocardium, have recently been documented to have great potential to differentiate into myogenic cells. These neo-myogenic cells in the myocardial scar tissue prevented ventricular dilatation and delayed cardiac dysfunction. Early clinical trials show encouraging data for cellular cardiomyoplasty. Although the beneficial effects of cell therapy for myocardial regeneration after an infarction have lead to phase I clinical trials, the mechanism of the novel therapy is often questioned. Replacing the scar tissue with muscle cells and stimulating neo-vessel formation in the implanted area have been proposed. However, a number of studies recently demonstrated that the survival rate of implanted cells was too low and that number of implanted cells decreased with time after transplantation. The number of surviving cells may not be enough to form adequate new muscle tissue to repair the damaged myocardium. We recently found that extracellular matrix in the myocardium plays an important role in maintaining the ventricular chamber size, and disruption of the matrix network may contribute to the apoptosis of cardiomyocytes leading to dilated cardiomyopathy. We implanted smooth muscle cells into the heart with dilated cardiomyopathy prior to ventricular dilatation. We found that implanted cells survived in the implanted area and altered myocardial matrix metabolism both within and remote from the region of implantation. Matrix metalloproteinase activity decreased in the transplanted group as compared with control group. The matrix structure was maintained and ventricular dilatation was prevented. These data suggest that implanted cells prevented ventricular dilatation through the alteration of matrix metabolism, which is a possible mechanism for implanted cells to improve heart function.

Autologous Bone Marrow Cell Transplantation Combined with Off-Pump Coronary Artery Bypass Grafting in Human Ischemic Myocardium

Recently, autologous bone marrow cell transplantation (CTx) for angiogenesis and myogenesis in ischemic myocardium has been extensively investigated to improve heart function. This study was designed to evaluate the effects of CTx with off-pump coronary artery bypass grafting (OPCAB) in patients who were not feasible for complete revascularization. Seven male patients underwent CTx combined with OPCAB in 5, CTx only in 1, and mitral valve repair in 1 patient simultaneously. Bone marrow was aspirated from iliac bone. Mean 1.5 x109 mononuclear cells including mean 7.3 x106 CD34+ cells and 2.4 x106 AC133+ cells were obtained and concentrated with 10cc. These cells were transplanted into non-graftable ischemic myocardium. Heart function was evaluated in all patients using MIBI scan, echocardiogram and heart magnetic resonance imaging (MRI) preoperatively. The effect of CTx was evaluated using MIBI scan, echocardiogram, and MRI postoperatively. An average of 2 grafts were bypassed. Other territories were transplanted with isolated mononuclear cell. All patients had an uncomplicated postoperative course. After 2 to 7 months follow-up, there was improvement in symptom, ejection fraction (from 43% to 47%) on echocardiogram and myocardial perfusion on MIBI scan and MRI in all patients. These preliminary data showed improvement of heart function and myocardial perfusion and also showed the feasibility and safety of combined therapy with OPCAB and CTx in ischemic myocardium. However, the effectiveness of CTx alone cannot be readily assessed. Further randomized, controlled studies are required to evaluate the effectiveness of CTx alone.

Smooth Muscle Cells Transplantation is better than Heart Cells Transplantation for Improvement of Heart Function in Dilated Cardiomyopathy

Muscle cell transplantation may delay or prevent cardiac dilation in dilated cardiomyopathy. The present study was designed to compare the effects of the heart function of smooth muscle cell (SMCs) auto-transplantation and heart cell (CMs) allo-transplantation in dilated cardiomyopathic hamsters, and to determine which cells are better for cell transplantation. CMs and SMCs were isolated from BIO 53.58 hamsters, and cultured for transplantation. CMs, SMCs (4 X 10(6) cells each) or culture medium were transplanted into 17 weeks old BIO 53.58 hamsters to achieve CM transplantation (CMTx), SMC transplantation (SMCTx), and controls (Con) (N=10 each). Cyclosporine (5 mg/Kg) was administered subcutaneously to CMTx. Healthy hamsters (sham, N=6) were used to compare heart functions. Four weeks after transplantation, heart function was evaluated in all groups using a Langendorff perfusion apparatus. Histology demonstrated severe focal myocardial necrosis in the dilated cardiomyopathic hearts. CMTx and SMCTx formed huge muscle tissue in the dilated myocardium. Sham, SMCTx, and CMTx had a better heart function than Con (p < 0.01), and SMCTx had a better peak systolic pressure (p < 0.05) and developed pressure (p < 0.05) than CMTx at any balloon volume. However, sham and SMCTx were not statistically different. SMCTx and CMTx formed muscle tissue and produced better heart function in the cardiomyopathic hearts, and SMCTx showed better systolic and developed pressures than CMTx, even though they were similar in other functions. Significantly, SMCTx had heart functions, which were similar to those of healthy hamster's hearts.