Abstract
Background: Valvular heart disease is an unfortunate part of the natural history of many congenital heart patients. Even with surgical interventions that use valvular replacements, pediatric patients with valvular dysfunction will likely require reoperations due to a progressive deterioration of graft durability and limited repair/growth potential. In order to address these concerns we sought to generate a biologically active pulmonary valve using patient-specific valvular cells and decellularized human pulmonary grafts. Methods and Results: Mesenchymal stem cells (MSCs) were generated from patient derived induced pluripotent stem (iPS) cells using culture conditions that favored an epithelial to mesenchymal transition. iPS-MSCs displayed CD105 and CD90 expression > 90% after four passages and could differentiate into osteocytes, chondrocytes and adipocytes (N=4). iPS-MSCs lacked expression of CD45 and CD34. Additionally, compared to bone marrow MSCs, iPS-MSC proliferated more readily (43 ± 1 vs 87 ± 1, p < 0.001) but maintained a gene expression profile >80% identical to bone marrow MSCs. Next, decellularized human pulmonary heart valves (provided by CryoLife®, Inc.) were seeded with iPS-MSCs using a combination of static and dynamic culture conditions. Repopulated pulmonary grafts were cultured up to 30 days. Immunohistochemistry demonstrated increased cellularity and presence of extracellular matrix components such as vimentin, proteoglycans and glycosaminoglycans in repopulated pulmonary valves compared to decellularized pulmonary valves, suggesting sustained cell function and maturation. Conclusions: Our results demonstrate the feasibility of constructing a biologically active human pulmonary valve using a sustainable and potent cell source. It is expected that once implanted, the bioactive pulmonary valve will have advantages over existing valvular replacements by its ability to remodel and grow in the repair of congenital defects.
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