AbstractsBiology & Animal Science

Human placenta derived cells for myocardial cell therapy

by Rajika Roy

Institution: Freie Universität Berlin
Degree: PhD
Year: 2014
Record ID: 1099744
Full text PDF: http://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000097860


Introduction: Autologous adult stem cells used for cellular therapy of ischemic heart disease have yielded modest results, partly because patient age and disease state affect the functionality of the transplanted cells. Neonatal donor cells may represent an attractive alternative for use in cardiac cell therapy, and the hypothesis that such cell products exert beneficial effects in a mouse model of ischemic heart disease was tested. In addition, the impact of heart failure-related humoral factors on neonatal progenitor cell behavior was studied to assess whether they would be affected by transplantation into a diseased recipient. Methods: Naïve amnion epithelial cells (AEC) and AEC induced to undergo epithelial-mesenchymal-transition induced (EMT-AEC) were evaluated in vitro for gene and protein expression profile, migration potential, cytokine secretion profile and gelatinase activity. The cardioprotective potential of AEC, EMT-AEC and clinical-grade placenta derived stromal cells (PLX-PAD) was evaluated in a mouse model of myocardial infarction. After four weeks cardiac function was evaluated by cardiac MRI, echocardiography and cardiac structure by histology and immunohistochemistry. To study the behavior of neonatal cells exposed to human heart failure (HF)-associated soluble factors, cord blood mesenchymal stromal cells (CB-MSC) were cultured in medium supplemented with HF serum instead of fetal bovine serum and analyzed for changes in growth kinetics, activation of stress signaling pathways and stimulation of apoptosis. Results: Transplantation of naïve AEC resulted in neither functional improvements nor a decrease in infarct size compared to infarcted control hearts. EMT-AEC displayed an MSC-like phenotype, enhanced migratory potential and extracellular matrix modulatory potential and upregulation of survival factors compared to AEC, in vitro. In vivo, transplantation of EMT-AEC resulted not only in functional improvements but also in decreased infarct size, independent of the support of angiogenesis and arteriogenesis. Transplantation of equivalent MSC-like clinical grade PLX-PAD cells also led to improved contractile function, decreased infarct size and aided in angiogenesis. However, HF patient serum depressed the proliferation kinetics of neonatal MSC and also activated stress signaling and pro-apoptotic signaling pathways. Conclusion: Progenitor cells from neonatal tissue sources exert cardioprotective effects in a mouse model of myocardial infarction, provided they display mesenchymal characteristics. Upon future transplantation in patients with heart failure, depression of neonatal progenitor cell function must be expected. Hintergrund: Die Verwendung autologer adulter Stammzellen für die Zelltherapie ischämischer Herzerkrankungen ergab bisher nur mäßige Funktionsverbesserungen, unter anderem weil Spenderalter und Krankheitszustand die Funktionalität der transplantierten Zellen beeinträchtigen. Neonatale Spenderzellen, unbeeinflusst von Alterungs- und Krankheitsprozessen, könnten eine…