Human umbilical cord blood-derived mononuclear cells improve murine ventricular function upon intramyocardial delivery in right ventricular chronic pressure overload

Abstract

IntroductionStem cell therapy has emerged as potential therapeutic strategy for damaged heart muscles. Umbilical cord blood (UCB) cells are the most prevalent stem cell source available, yet have not been fully tested in cardiac regeneration. Herein, studies were performed to evaluate the cardiovascular safety and beneficial effect of mononuclear cells (MNCs) isolated from human umbilical cord blood upon intramyocardial delivery in a murine model of right ventricle (RV) heart failure due to pressure overload.MethodsUCB-derived MNCs were delivered into the myocardium of a diseased RV cardiac model. Pulmonary artery banding (PAB) was used to produce pressure overload in athymic nude mice that were then injected intramyocardially with UCB-MNCs (0.4 × 10^6 cells/heart). Cardiac functions were then monitored by telemetry, echocardiography, magnetic resonance imaging (MRI) and pathologic analysis of heart samples to determine the ability for cell-based repair.ResultsThe cardio-toxicity studies provided evidence that UCB cell transplantation has a safe therapeutic window between 0.4 to 0.8 million cells/heart without altering QT or ST-segments or the morphology of electrocardiograph waves. The PAB cohort demonstrated significant changes in RV chamber dilation and functional defects consistent with severe pressure overload. Using cardiac MRI analysis, UCB-MNC transplantation in the setting of PAB demonstrated an improvement in RV structure and function in this surgical mouse model. The RV volume load in PAB-only mice was 24.09 ± 3.9 compared to 11.05 ± 2.09 in the cell group (mm3, P-value <0.005). The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5. Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC’s transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.ConclusionsThese findings indicate that human UCB-derived MNCs promote an adaptive regenerative response in the right ventricle upon intramyocardial transplantation in the setting of chronic pressure overload heart failure.

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…The advantages and limitations of each stem cell with regard to the possible emergence of ethical concerns (symbolized by ¥), the invasiveness and collection (from + to ++++), the isolation procedure, the abundance (from + to ++++), expansion and proliferation rate, the transdifferentiation capacity, the paracrine effects or/and cardiomyogenic potential, the survival and engraftment capacity as well as the immunogenic, oncogenic or teratogenic risks is given in the accessory side tables. The left table abridges bone marrow-derived stem cells [3,[19][20][21]27,28], cortical bone-derived stem cells [32,33], adipose tissue-derived stem cells [34,37,39,41] and gestation-related stem cells [42][43][44][45][46][47][48][49]51,54] and the right table abridges cardiac stem cells [57,59,60], skeletal muscle stem cells [62,63,66] and induced pluripotent stem cells [67,[69][70][71]. The human body scheme was constructed with images sourced from Servier Medical Art (http://www.servier.com/ Powerpoint-image-bank) and Cientic website (http://www.cientic.com/).…”

“…Pregnancy byproducts represent an important source of stem cells which can be obtained from a plethora of sources, such as placenta [42][43][44], chorionic plate [45], amniotic fluid [46], umbilical cord [47,48] and its blood [48][49][50][51]. These immune-privileged materials offer several advantages (Fig.…”

“…This would be particularly important for elder patients, whose stem cell quality is expected to reduce with age [12]. Similarly to the above stem cell groups, it is thought that these cells act mainly through paracrine activity, stimulating vascularization, cardiomyogenesis, and inhibiting inflammation, fibrosis and apoptosis [42][43][44][45]47,48,51]. Also related to gestation, MSCs obtained from fetal heart tissue (fC-MSC) and embryonic stem cells (ESC) have been proposed as alternative multipotent cells with the ability to differentiate into CMs, endothelial and smooth muscle cells.…”

“…If the cell therapy is to be tested in the treatment of right ventricular (RV) chronic pressure overload, then the pulmonary artery banding is an alternative to test stem cell preventive effects of RV dilation. Given the chronic nature of the pathology, cell administration should be ensued not before 4 weeks post-surgical intervention [51,55]. With regard to the conditions affecting left ventricle (LV), one can develop models of AMI, chronic myocardial infarction (CMI), chronic myocardial ischemia and HF by two main routes.…”

“…The final, yet the most compromising, issue in clinical translation is related to the therapy monitoring, particularly the molecular analysis, which is performed post-mortem in animal models by, for instance, histological and immunohistochemical analysis as well as by PCR and western blot techniques making use of heart tissue samples [3,8,15,16,21,22,29,34,38,41,51,54,61,62,64,105,109,110,119]. Only Chen et al [103].…”