| Summary: | Non-ischaemic right ventricular dysfunction and cardiac failure is a source of considerable morbidity in children with congenital heart disease. Despite an increasing body of evidence suggesting that the intrinsic regenerative capacity of the heart can be encouraged by stimulation of resident cardiac stem cells or the transplantation of extracardiac progenitor cells, cell transplantation has not previously been studied in the paediatric setting where enhancing the function of the ventricle in response to supraphysiological workloads might be beneficial. Firstly I studied extra-cellular matrix composition, myocyte homeostasis and gene expression in right ventricular biopsies obtained from patients with Hypoplastic Left Heart Syndrome (HLHS) undergoing neonatal surgical palliation and from patients undergoing neonatal truncus arteriosus repair in order to investigate potential differences in the myocardial substrate which could have implications for adaptive growth potential and haemodynamic performance in HLHS. Simultaneous to these activities, I collected, isolated and analysed umbilical cord blood stem cells from children born with either structurally-normal hearts or HLHS to investigate whether such cell populations might be useful in cardiac augmentation. We then transplanted human cord blood stem cells from normal cord blood donors into an immunosuppressed neonatal sheep model of right ventricular training, taking load-independent functional measurements at baseline and again after one month. Transplanted human cells were detected in the myocardium, spleen, kidney and bone marrow up to 6 weeks after transplantation. Human cells expressed the haematopoietic marker CD45 and in the bone marrow and spleen, also the mature B cell marker CD23. Significant functional improvements were seen in the group receiving human cord blood stem cells compared to placebo. Data demonstrated that lineage negative-enriched cord blood stem cells engraft and adopt traditional haematopoietic cell fates in both myocardium as well as natural niches such as bone marrow and spleen.
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