1, dilated cardiomyopathy in children is a serious health risk for children, and there is no specific treatment. Dilated cardiomyopathy (DCM) is a type of cardiomyopathy of unknown cause, the incidence of which is about 84/100,000 people in China.The course of DCM is progressive and the prognosis is very poor, seriously endangering the health of children, with a survival rate of 60%-90% at 1 year and 20%-80% at 5 years.DCM mainly manifests as unilateral or bilateral enlargement of the heart chambers, systolic function of the heart The pathology of DCM is characterized by unilateral or bilateral enlargement of the cardiac chambers, systolic function of the heart, hypertrophy of myocardial fibers, nuclei consolidation, deformation or disappearance, and increased fibrous tissue.
At present, there is no specific treatment for DCM, and basic medications including digitalis, diuretics, vasodilators, neuroendocrine blockers, growth hormones, and high-dose immunoglobulins can improve the prognosis of some children with DCM, but still cannot solve the problem at the root. Although some researchers believe that left ventricular decompensation can significantly improve left ventricular function, the in-hospital mortality rate is still as high as 10-20% and the 2-year survival rate is only 60%; almost 50% of symptomatic pediatric cardiomyopathy patients require heart transplantation or die within 2 years. Therefore, innovative exploration of new methods for the treatment of pediatric DCM is of great clinical significance to improve the prognosis of pediatric DCM.
2. Cytogenic cardiomyoplasty offers new therapeutic hope for pediatric DCM. By integrating carbon 14 into cardiomyocyte DNA to determine the age of cardiomyocytes, Bergmann et al. found that no less than 50% of cardiomyocytes showed carbon 14 exchange during a normal life cycle, confirming that human cardiomyocytes have the ability of self-renewal; this provides a strong theoretical basis for myocardial regeneration therapy.
Encouraging advances have been made in myocardial regeneration therapies for ischemic and non-ischemic heart disease, including stem cell transplantation, growth factor and gene transfer, and genetic engineering of cardiac tissue. The seed cells for transplantation include skeletal muscle myogenic cells, bone marrow cells, circulating blood-derived precursor cells, endometrial mesenchymal stem cells, adult testicular tissue pluripotent stem cells, mesothelial stem cells, adipose-derived stromal stem cells, embryonic stem cells, induced pluripotent stem cells and bone marrow mesenchymal stem cells.
How to choose seed cells for transplantation depends on the type of primary disease; those with acute myocardial infarction should choose seed cells that can reduce myocardial necrosis and increase blood flow; while those with heart failure should choose seed cells that can replace or promote myocardial regeneration, reverse myocardial apoptotic mechanisms and activate stromal cell processes. Transplanted seed cells improve ventricular function by reducing the extent of myocardial infarct scarring and fibrosis, improving myocardial activity, limiting local ventricular dilation, and improving ventricular compliance and paracrine effects. The data show a significant dose-effect relationship between the improvement in cardiac function and the number of transplanted seed cells entering the target tissue area.
The process by which transplanted seed cells enter the target tissue region is called cell homing, and the number of cells homing determines the effect of cell transplantation; while cell homing to the active neovascular region is a complex process that depends on the interaction between chemoattractants (e.g., stromal cell-derived factor-1), chemoattractant receptors, intercellular signaling, adhesion molecules, and proteases.
Currently, gap junctions and electrical information exchange between cardiomyocytes and transplanted seed cells in the heart itself have not been observed; also, the death of transplanted seed cells severely affects the effectiveness of cell transplantation, which may be due to ischemia, apoptosis, and inflammatory responses. Therefore, the development of techniques to improve cell survival and differentiation, such as tissue engineering techniques, prevascularization techniques, and pre-adaptation techniques, is significant to improve the effectiveness of cell transplantation.
Indications or potential indications for cell-based cardiomyoplasty are myocardial infarction, idiopathic DCM, diabetic cardiomyopathy, Chagas disease, ischemic mitral regurgitation, myocardial densification insufficiency, pediatric cardiomyopathy, and surgical ventricular reconstruction-related disease. Non-ischemic cardiomyopathies have been found to derive greater benefit from cytogenic cardiomyoplasty than ischemic cardiomyopathies. Cytogenic myocardioplasty has been successfully used with heart-pounding results in small animal models, canine models of idiopathic and adriamycin DCM, with clinical trials already underway in patients with idiopathic DCM.
The transplanted seed cells survive well in these host myocardium, presumably because myocardial perfusion is not as severely disrupted in non-ischemic cardiomyopathy as in patients with ischemic cardiomyopathy. Considering that the etiology of pediatric DCM patients differs from that of adults, pediatric DCM patients are better suited as ideal indications for cytotropic cardiomyoplasty, and they are more likely to benefit from this technique. Studies have shown that MSCs, embryonic stem cells and induced pluripotent differentiated stem cells can be used as seed cells for pediatric cardiomyopathy patients.
3. Umbilical cord blood MSCs are feasible as seed cells for cellular cardiomyoplasty in pediatric DCM patients.
Theoretically, embryonic stem cells and induced pluripotent differentiated stem cells are ideal seed cells for cellular cardiomyoplasty in pediatric patients with cardiomyopathy; however, the source of the former is limited and there may be ethical issues; while the latter requires the addition of induction substances during the culture process and the effect of the culture medium itself on seed cells as well as on cardiomyocytes has not been clarified, thus greatly limiting their clinical application and mostly limited to animal experiments The clinical application of the latter has been limited to animal studies. Mesenchymal stem cells (MSCs) are a class of multipotent differentiated stem cells with the ability to self-renew and are found in the bone marrow and many other tissues of adults.
MSCs can be isolated from bone marrow and can differentiate into a variety of cells, such as bone cells, adipocytes, chondrocytes muscle cells and tendon cells. Therefore, MSCs in bone marrow are known as universal donor cells. In recent years, the application of bone marrow MSCs transplantation to repair damaged myocardium has become a hot research topic at home and abroad; numerous studies have confirmed that MSC transplantation can inhibit the inflammatory response within the myocardium, inhibit apoptosis of cardiomyocytes, and stimulate intra-myocardial revascularization; there are obvious therapeutic effects in animal models of DCM, and in clinical studies, MSC transplantation can significantly improve ventricular In clinical studies, MSC transplantation can significantly improve ventricular function in adults with DCM.
However, the source of bone marrow MSCs is limited and access to them is invasive; the differentiation potential of bone marrow MSCs decreases with age; in addition, the conversion of induced bone marrow MSCs into cardiomyocytes is less efficient. Bone marrow aspiration is extremely inconvenient for children and is not well accepted by children and parents, while the amount of bone marrow aspirated from pediatric patients is low. The above factors greatly limit the promotion of bone marrow MSCs transplantation in pediatric DCM patients, and also seriously affect the transplantation outcome of bone marrow MSCs.
4. The rationale for transplantation of cord blood MSCs by the peripheral intramuscular injection route for the treatment of childhood DCM.
It has been demonstrated that the injection of seed cells through the intravenous system is not useful for myocardial regeneration, because most of the input cells stay in the lungs, liver and spleen and do not home to the myocardial tissue. Currently, the main transplantation routes for cellular myocardioplasty seed cells are the epicardial route, the endocardial route, and the intracoronary route. The epicardial route is mainly achieved by surgical, thoracoscopic and robotic techniques, which have the advantage of good exposure of the transplantation area, precise injection site and multi-point injection; however, this technique requires patients to bear the risks associated with general anesthesia and the procedure itself, and is particularly difficult to achieve in pediatric DCM patients.
Both the endocardial and intracoronary routes are catheter-based cell transplantation techniques that are less invasive, relatively simple, and can be repeated multiple times, but both require pediatric patients to undergo general or local anesthesia and the risks associated with the catheterization procedure itself, especially the complications associated with the latter, such as severe arrhythmias and vascular injury. In the endocardial route, it is relatively difficult to locate the transplanted area within the ventricle with the cardiac catheter, and the effect of transplantation is weakened by the large loss of seed cells during injection; while in the intracoronary route, it is unclear whether the seed cells can theoretically migrate through the basement membrane of the vessel into the myocardium, and this technique has the risk of inducing microembolism.
In addition, all three routes can cause new, harmful scar tissue and calcification in the heart, which can induce new severe arrhythmias and further deteriorate cardiac function. Therefore, there is an urgent need to develop seed cell implantation methods that are less invasive, do not require anesthesia, are simple to perform, can be repeatedly implanted, are safe, and are suitable for pediatric DCM patients.
Intramuscular injection of MSCs has been shown to improve myotonic dystrophy, and therefore patients with dystrophy with cardiomyopathy are more suitable for intramuscular injection of MSCs; previous studies have confirmed that MSCs injected intramuscularly into skeletal muscle do not migrate to other tissues. Newly, Shabbir et al. took full advantage of the trophic effect of bone marrow MSCs and innovated a new non-invasive method of stem cell input with the help of a hamster model of dilated cardiomyopathy.
Namely, intramuscular injection of MSCs and MSCs conditioned cultures revealed a 40% increase in cardiac short-axis shortening, 30% and 80% increase in myocardial tissue capillary and myocardial nuclei density, respectively, a 60% reduction in myocardial apoptosis and a 50% reduction in myocardial fibrosis 1 month after MSCs transplantation; evidence of myocardial cell regeneration showed that cell cycle markers (Ki67 and phosphorylated histone H3) expression was increased 2-fold and cardiomyocyte diameter was reduced by an average of 13%; circulating levels of hepatocyte growth factor, leukemia transplantation factor, and macrophage monoclonal stimulating factor were significantly increased.
Yoo et al. found no significant differences in secreted factors between MSCs derived from adult bone marrow, testicular tissue, cord blood and umbilical cord tissue, and no changes in the expression of hepatocyte cell growth factor, transforming growth factor beta and cyclooxygenase-1 (COX-1) and COX-2. It is suggested that MSCs of umbilical cord blood origin and MSCs of bone marrow origin have similar trophic effects. Therefore, implantation of umbilical cord blood MSCs through the peripheral muscle route has a promising potential to utilize the nutritional and paracrine effects of umbilical cord blood MSCs for the treatment of DCM in children.