Advances in research on mechanisms related to myocardial regeneration in neonatal murine / 中国比较医学杂志

Cardiovascular disease is a health hazard to humans and systolic heart failure due to myocardial infarction is a major cause of death.It was previously thought that myocardial cells of the adult mammalian heart possess a limited ability to proliferate and self-renew.However,it has been widely reported that mammals have the ability to regenerate the myocardium,which is restricted to early postnatal life,and that it is strong enough to repair damaged heart tissue.The discovery of myocardial regeneration in neonatal hearts has provided an ideal animal model to investigate the mechanisms that affect myocardial regeneration,and many mechanisms that reverse myocardial cell cycle arrest and promote myocardial regeneration have been revealed.In this article,we review the factors affecting gene expression for myocardial regeneration(e.g.,ncRNAs and transcription factors),myocardial regeneration-related signaling pathways,and the regulation of myocardial regeneration by non-myocardial cells(e.g.,extracellular matrix,immune response,and epicardium)to provide directions for achieving myocardial regeneration after myocardial injury in adult mammals.

Establishment and application of animal models of myocardial infarction / 解剖学报

Myocardial infarction is one of the severe cardiovascular diseases.The patients with myocardial infarction die of heart failure or arrhythmia.In recent years,the studies in myocardial infarction therapies have advanced greatly,especially the preclinical experimental studies.The experimental studies of myocardial infarction often rely on animal models.Therefore,successful establishment of the myocardial infarction models has important application value in exploring the new techniques and measures for repairing the infarcted myocardium.In this paper,the techniques in establishment of the myocardial infarction models and strategies of their application are summarized.

The synchronous mechanism of myocardial regeneration-cell disintegration-myocardial fibrosis and its relationship with heart failure / 中华胸心血管外科杂志

Objective@#To observe the cardiomyocytes regeneration after myocardial infarction in Chinese small pigs, analyze the mechanism of myocardial fibrosis after myocardial regeneration.@*Methods@#Nine Chinese small pigs, weight 18-20 kg, 6 pigs in the experimental group(to ligate LAD at the equal blood flow point), and 3 in the control group(no any operation was performed). Monitor the hemodynamics of the left ventricle. Cardiac specimens were taken after 4 weeks of LAD ligation, the left ventricle was divided into 17 segments, and fixed in 4% paraformaldehyde for 1 week. Hematoxylin-Eosin/(HE) staining, PTAH、Ki-67-DAB and α-sarcomeric-actin-DAB staining for pathological observation.@*Results@#Four weeks of LAD ligation, different range of infarct size could be found in all the 17 segment of left ventricle. There was significant systolic pressure difference between the proximal and distal part in the left ventricular cavity. After 4 weeks of LAD ligation, there were a large number of new cardiomyocytes around the infarction area, which connected with the original mature cardiomyocytes directly. Large number of disassembled cardiomyocytes in the infarcted area and myocardial fibers were broken, cell structure disappeared, and nuclei were scattered in fibrotic tissues.@*Conclusion@#New cardiomyocytes after myocardial infarction were derived from the mature cardiomyocytes. Myocardial regeneration, cell disintegration, and myocardial fibrosis were performed synchronously under the influence of myocardial tension.

The synchronous mechanism of myocardial regeneration-cell disintegration-myocardial fibrosis and its relationship with heart failure / 中华胸心血管外科杂志

Objective To observe the cardiomyocytes regeneration after myocardial infarction in Chinese small pigs, ana-lyze the mechanism of myocardial fibrosis after myocardial regeneration. Methods Nine Chinese small pigs, weight 18-20 kg, 6 pigs in the experimental group( to ligate LAD at the equal blood flow point) , and 3 in the control group( no any operation was performed) . Monitor the hemodynamics of the left ventricle. Cardiac specimens were taken after 4 weeks of LAD ligation, the left ventricle was divided into 17 segments, and fixed in 4％ paraformaldehyde for 1 week. Hematoxylin-Eosin/( HE) stai-ning,PTAH、Ki-67-DAB and α-sarcomeric-actin-DAB staining for pathological observation. Results Four weeks of LAD liga-tion, different range of infarct size could be found in all the 17 segment of left ventricle. There was significant systolic pressure difference between the proximal and distal part in the left ventricular cavity. After 4 weeks of LAD ligation, there were a large number of new cardiomyocytes around the infarction area, which connected with the original mature cardiomyocytes directly. Large number of disassembled cardiomyocytes in the infarcted area and myocardial fibers were broken, cell structure disap-peared, and nuclei were scattered in fibrotic tissues. Conclusion New cardiomyocytes after myocardial infarction were derived from the mature cardiomyocytes. Myocardial regeneration, cell disintegration, and myocardial fibrosis were performed synchro-nously under the influence of myocardial tension.

Role of Notch signaling in the mammalian heart

Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair.

Asistencia y regeneración del miocardio combinando terapia celular e ingeniería de tejidos. Resultados del estudio clínico MAGNUM / Myocardial regeneration and asistance combined cardiac tissue engineering and stem cell therapy. Outcome of trial MAGNUM

Objetivos. El trasplante celular para la regeneración del miocardio está limitado por la escasa viabilidad del injerto y la baja retención celular. En la miocardiopatía isquémica la matriz extracelular está profundamente alterada, por consiguiente, sería importante asociar un procedimiento para regenerar las células miocárdicas y restaurar la función de la matriz extracelular. En este estudio clínico, fue evaluada la terapia celular intrainfarto asociada a una matriz de colágeno sembrada con células e implantada sobre ventrículos infartados.Métodos. En 15 pacientes (54,2±3,8 años de edad) que presentaban cicatrices miocárdicas postisquémicas en el ventrículo izquierdo (VI) y con indicación de cirugía de revascularización miocárdica, se implantaron, durante la operación, células de la médula ósea mononucleares autólogas (CMO) en la cicatriz. Se agregó sobre esa zona infartada una matriz de colágeno tipo I con el mismo número de CMO

Resultados. No hubo mortalidad ni eventos adversos relacionados (seguimiento 15±4,2 meses). La clase funcional según la New York Heart Association (NYHA) mejoró de 2,3±0,5 a 1,4±0,3 (p=0,005). El volumen de fin de diástole del VI evolucionó de 142±24 a 117±21 mL (p=0,03), el tiempo de desaceleración del llenado del VI mejoró aumentando de 162±7 mseg a 196±8 mseg (p=0,01). El espesor del área cicatrizada progresó de 6±1,4 a 9±1,5 mm (p=0,005). La fracción de eyección (FE) mejoró de 25±7 a 33±5% (p=0,04).Conclusiones. La inyección intramiocárdica de células de médula ósea y la fijación simultánea de una matriz sembrada con progenitores celulares (stem cells) sobre el epicardio fue simple y sin complicaciones. La matriz de colágeno aumento el espesor de la zona del infarto con nuevos tejidos viables, limitando la dilatación ventricular y mejorando la función diastólica. Estos resultados positivos no pueden ser absolutamente relacionados a las células y la matriz, pues se asociaron puentes de revascularización coronaria. En conclusión, la ingeniería de tejidos puede extender las indicaciones y beneficios de la terapia con células madre en cardiología, convirtiéndose en un camino prometedor para la creación de un “miocardio bioartificial”

Objectives. Stem cell therapy for myocardial regeneration is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy the extracellular matrix is pathologically modified, therefore it could be important to associate a procedure aiming at regenerating both, myocardial cells and the extracellular matrix. We evaluated intrainfarct cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted hearts.Methods. In 15 patients (aged 54.2±3.8 years) presenting LV postischemic myocardial scars and with indication for a single off-pump-CABG, autologous mononuclear bone marrow cells (BMC) were implanted during surgery in the scar. A 3D collagen type I matrix seeded with the same number of BMC was grafted onto the infarction zone.Results. There was no mortality and any related adverse events (follow-up 15±4.2 months). NYHA FC improved from 2.3±0.5 to 1.4±0.3 (p=0.005). LV end-diastolic volume evolved from 142±24 to 117±21 mL (p=0.03), LV filling deceleration time improved from 162±7 ms to 196±8 ms (p=0.01). Scar area thickness progress from 6±1.4 to 9±1.5mm (p=0.005). EF improved from 25±7 to 33±5% (p=0.04).Conclusions. Simultaneous intramyocardial injection of mononuclear bone marrow cells and fixation of a BMC-seeded matrix onto the epicardium is feasible and safe. The cell seeded collagen matrix seems to increase the thickness of the infarct scar with viable tissues and help to normalize cardiac wall stress in injured regions, thus limiting ventricular remodelling and improving diastolic function. Patients’ improvements can not be conclusively related to the cells and matrix due to the association of CABG. Cardiac tissue engineering should extend the indications and benefits of stem cell therapy in cardiology, becoming a promising way for the creation of a “bioartificial myocardium”

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.

Stem Cell Research in Cardiovascular System / 대한해부학회지

Myocardial infarction leads to loss of tissue and impairment of cardiac performance. Because cardiomyocytes have a limited ability to self-renewal, and thus the transplantation of adult stem cells into infarcted region is a promising therapy to regenerate damaged cardiac tissue. Stem cells for myocardial regeneration are mesenchymal- and hematopoietic stem cells derived from bone marrow, or skeletal myoblasts in animals, and these stem cells generated cardiomyocytes and endothelial cells in the infarcted regions, and improved cardiac function. Clinical data showed that autologous mesenchymal stem cells and skeletal myoblasts increased ejection fraction and blood flow, and decreased infarct size in patients. Some researchers have used a different strategy that cytokine-mobilized bone marrow cells or angioblasts homed to the infarcted region, replicated, differentiated, and improved cardiac function. The current trend is the combined use of cytokine treatment and cell transplantation to increase the efficiency of myocardial regeneration. In addition, genetic manipulation of adult stem cells has been done to express cardioprotective recombinant proteins, or enhance angiogenesis in animal study. Thus cellular transplantation, cytokine induction and gene therapy should not be viewed as competitive but rather as complementary with the common and final goal of improving the outcome of heart failure patients. In this review, we will discuss about studies for myocardial repair in animal and in patients.

Repair of infarcted myocardium by intramyocardial transplantation of mobilized autologous bone marrow stem cells in humans / 中国病理生理杂志

AIM: To investigate the effects of in situ transplantation of mobilized autologous bone marrow stem cells on infarction size and cardiac function in patients with acute myocardial infarction. METHODS:25 patients with first acute myocardial infarction were randomly divided into stem cells in situ transplantation group and control group, 12 patients in stem cells in situ transplantation group were injected subcutaneously with 300 ?g granulocyte colony-stimulating factor(G-CSF) daily for four days in addition to standard therapy. 13 patients in control group were treated with standard therapy alone. The conventional 12 leads electrocardiogram were recorded on 1, 28 days after admission and the cardiac function was scored by the QRS scoring system proposed by Wagner. Furthermore, the infarction size was assessed by radionuclide myocardial perfusion imaging 7, 28 days after admission. RESULTS:4 weeks after admission, the QRS scores decreased, the infarction size reduced significantly in the stem cells in situ transplantation group (from 36.0%?8.3% to 18.0%?5.8%, P