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Objective: Cell-based therapies utilizing mesenchymal and cardiac progenitor cells have demonstrated promising results in the treatment of congenital heart disease. We hypothesize that autologous human placental-derived progenitor cells share similar characteristics to cardiac progenitor cells (CPC) derived from autologous bone marrow or cardiac sources.Methods: Fetal portion of the placenta was harvested at the time of delivery from newborns (N = 5), and cells were isolated and expanded from the amnion and chorion layers. Flow cytometry and multi-lineage differentiation potential assays were used to characterize placental-derived progenitor cells. Placenta derived sphere cells were generated and phenotypic and functional characteristics were analyzed.Results: CD90, CD105, and Vimentin were expressed in <10% placental-derived progenitor cells, and differentiation into mesodermal lineages was not observed. However, placental-derived progenitor cells were able to differentiate into smooth muscle and cardiomyocyte lineages. In placenta derived sphere cells, >65% expressed cardiac lineage marker (SIRPA), but <15% expressed Discoidin domain receptor 2 (DDR2). Compared to placental-derived progenitor cells, placenta derived sphere cells expressed higher levels of cardiac transcription factors, cardiac ion channel genes and cardiac structural genes.Conclusions: Placental progenitor cells demonstrate similar characteristics to CPC currently utilized in several clinical trials that can serve as a readily available autologous source for cardiac cell therapy.