Changqing Zhou

Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction

•  Introduction •  Transdifferentiation ‐  MSCs differentiate into cardiomyocytes ‐  MSCs differentiate into vascular cells •  Paracrine effects ‐  Endogenous cardiac regeneration induced by paracrine effects ‐  Neovascularization induced by paracrine effects ‐  Anti‐inflammatory effect of MSCs ‐  Anti‐apoptotic effects by MSCs ‐  Cardiac remodelling induced by paracrine effects ‐  Paracrine‐mediated cardiac contractility ‐  Cardiac metabolic modulation by MSCs •  Other potential effects ‐  Cardiac nerve sprouting ‐  Anti‐arrhythmic potential •  Conclusion

Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators

•  Introduction •  MiRNAs and MSC differentiation into cardiovascular cells ‐  MiRNAs and MSC differentiation into CMCs ‐  MiRNAs and MSC differentiation into vascular cells •  MiRNAs and MSC‐mediated paracrine effects ‐  MiRNAs and MSC‐mediated endogenous cardiac regeneration ‐  MiRNAs and MSC‐mediated cardiac contractility ‐  MiRNAs and MSC‐mediated neovascularization ‐  MiRNAs and MSC‐mediated anti‐inflammatory effect ‐  MiRNAs and MSC‐mediated anti‐apoptotic effect ‐  MiRNAs and MSC‐mediated anti‐remodelling effect ‐  MiRNAs and MSC‐mediated cardiac metabolic effect •  MiRNAs and MSC‐mediated other potential effects ‐  MiRNAs and MSC‐related cardiac neurogenesis ‐  MiRNAs and MSC anti‐arrhythmic potential •  Preconditioning MSCs with MiRNAs as therapeutic perspectives •  Future directions and concluding remarks

Cardiac Stem Cells and their Roles in Myocardial Infarction

Myocardial infarction leads to loss of cardiomyocytes, scar formation, ventricular remodeling and eventually deterioration of heart function. Over the past decade, stem cell therapy has emerged as a novel strategy for patients with ischemic heart disease and its beneficial effects have been demonstrated by substantial preclinical and clinical studies. Efficacy of several types of stem cells in the therapy of cardiovascular diseases has already been evaluated. However, repair of injured myocardium through stem cell transplantation is restricted by critical safety issues and ethic concerns. Recently, the discovery of cardiac stem cells (CSCs) that reside in the heart itself brings new prospects for myocardial regeneration and reconstitution of cardiac tissues. CSCs are positive for various stem cell markers and have the potential of self-renewal and multilineage differentiation. They play a pivotal role in the maintenance of heart homeostasis and cardiac repair. Elucidation of their biological characteristics and functions they exert in myocardial infarction are very crucial to further investigations on them. This review will focus on the field of cardiac stem cells and discuss technical and practical issues that may involve in their clinical applications in myocardial infarction.

Improvements of cardiac electrophysiologic stability and ventricular fibrillation threshold in rats with myocardial infarction treated with cardiac stem cells

Objectives:Arrhythmia is of concern after cardiac stem cell transplantation in repairing infarcted myocardium. However, whether transplantation improved the ventricular fibrillation threshold and whether severe malignant ventricular arrhythmia is induced in the myocardial infarction model are still unclear. We sought to investigate the electrophysiologic characteristics and ventricular fibrillation threshold in rats with myocardial infarction by treatment with allogeneic cardiac stem cells. Design:Prospective, randomized, controlled study. Setting:University-affiliated hospital. Subjects:Male Sprague-Dawley rats. Interventions:Myocardial infarction was induced in 20 male Sprague-Dawley rats. Two weeks later, animals were randomized to receive 5 × 106 cardiac stem cells labeled with PKH26 in phosphate buffer solution or a phosphate buffer solution-alone injection into the infarcted anterior ventricular-free wall. Measurements and Main Results:Six weeks after the cardiac stem cell or phosphate buffer solution injection, electrophysiologic characteristics and ventricular fibrillation threshold were measured at the infarct area, infarct marginal zone, and noninfarct zone. Labeled cardiac stem cells were observed in 5-&mgr;m cryostat sections from each harvested heart. The unipolar electrogram activation recovery time dispersions were shorter in the cardiac stem cell group compared with those at the phosphate buffer solution group (15.5 ± 4.4 vs. 38.6 ± 14.9 msecs, p = .000177). Malignant ventricular arrhythmias were significantly (p = .00108) less inducible in the cardiac stem cell group (one of ten) than the phosphate buffer solution group (nine of ten). The ventricular fibrillation thresholds were greatly improved in the cardiac stem cell group compared with the phosphate buffer solution group. Labeled cardiac stem cells were identified in the infarct zone and infarct marginal zone and expressed Connexin-43, von Willebrand factor, &agr;-smooth muscle actin, and &agr;-sarcomeric actin. Conclusions:Cardiac stem cells may modulate the electrophysiologic abnormality and improve the ventricular fibrillation threshold in rats with myocardial infarction treated with allogeneic cardiac stem cells and cardiac stem cell express markers that suggest muscle, endothelium, and vascular smooth muscle phenotypes in vivo.

Cardiac stem cells transplantation enhances the expression of connexin 43 via the ANG II/AT1R/TGF-beta1 signaling pathway in a rat model of myocardial infarction ☆

BACKGROUND In this study, we hypothesized that CSCs mediated the expression of Cx43 after transplantation post MI via the ANG II/AT1R/TGF-beta1 signaling pathway. METHODS Myocardial infarction (MI) was induced in twenty male Sprague-Dawley rats. The rats were randomized into two groups and were then received the injection of 5 × 10(6) CSCs labeled with PKH26 in phosphate buffer solution (PBS) or equal PBS alone into the infarct anterior ventricular free wall two weeks after MI. Six weeks later, relevant signaling molecules involved were all examined. RESULTS In the CSCs group, an increased expression of Cx43 could be observed in different zones of the left ventricle (P<0.01). There was a significant reduction of the angiotensin II (ANG II) level in plasma and different regions of the left ventricular cardiac tissues (P<0.05; P<0.01). The angiotensin II type I receptor (AT1R) was decreased accompanied with an enhanced expression of angiotensin II type II receptor (AT2R) (P<0.01). Transforming growth factor beta-1(TGF-beta1) was downregulated (P<0.01). The expression of mothers against decapentaplegic homolog (SMAD) proteins including SMAD2 and SMAD3 was attenuated whereas SMAD7 was elevated (P<0.01, P<0.01, P<0.05). In addition, the expression of mitogen-activated protein kinases (MAPKs) including extracellular kinases 1/2 (ERK1/2) and p38 was also found to be reduced (P<0.01). CONCLUSION CSCs transplantation could enhance the level of Cx43 after MI. They might function through intervening the ANGII/AT1R/TGF-beta1 signaling pathway to regulate the expression of Cx43.

Mesenchymal Stem Cells Enhanced Cardiac Nerve Sprouting via Nerve Growth Factor in a Rat Model of Myocardial Infarction

BACKGROUND Transplantation of mesenchymal stem cells (MSCs) alters the ventricular electrophysiologic properties after myocardial infarction (MI) in rats. However, it is unclear whether MSCs transplantation enhances the secretion of nerve growth factor (NGF) and affects cardiac sympathetic remodeling. METHODS MI was induced in 35 male Sprague-Dawley rats. Two weeks later, the animals were randomized to MSCs or phosphate buffer solution (PBS) injections into the infarcted myocardium. Six weeks thereafter, the expressions of NGF, growth associated protein 43 (GAP43) and tyrosine hydroxylase (TH) were measured and the density of GAP43 and TH positive nerves was calculated in the borderzone. NGF levels were detected in different culture conditions with neonatal rat ventricular myocytes (NRVMs, 2 × 10(5)/well) and MSCs (2 × 10(5)/well). RESULTS Compared with PBS, mRNA expression and protein levels of NGF, GAP43 and TH increased in the border zone after MSCs injection. Immunohistochemistry showed more GAP43- and TH-positive nerves in the MSCs than in the PBS group. Compared to monocultured MSCs, mono-cultured NRVMs secreted more NGF in vitro. CONCLUSIONS The expression of NGF increased after MSCs transplantation, which may affect sympathetic remodeling and the electrophysiological properties after MI. Paracrine factors secreted by MSC-CM may be involved in this process.

Long noncoding RNAs: Novel molecules in cardiovascular biology, disease and regeneration

Remarkable breakthroughs made in genomic technologies have facilitated the discovery of thousands of novel transcripts that do not template protein synthesis. Numerous RNAs termed as long noncoding RNAs (lncRNAs) generated from this pervasive transcription function vividly in gene regulatory networks and a variety of biological and cellular processes. Here, we make a brief description of the known and putative functions of lncRNAs in cardiovascular biology and disease. The association between lncRNAs and stem cells mediated cardiomyocytes differentiation and neovascularization is discussed then. It will provide a new clue for further studies on these novel molecules in cardiovascular disease and bring bright prospects for their future applications in cardiac regenerative medicine.