Introduction: The developmental origin of the c-kit+ cardiac progenitor cell (CPC) pool in the adult heart has remained elusive. Recently, it has been discovered that the injured heart is enriched with c-kit+, which also express the hematopoietic marker CD45. We characterize the phenotype and transcriptome of this atrial appendage enriched cell population, which is defined as a resident macrophage population. The c-kit+/CD45+ progenitor cell population can activate EMT, Neural Crest and Pluripotency associated pathways in vitro, in conjuction with CD45 down-regulation, and acquire a transient c-kit+/lin- cell state. This pontaneous reprogramming process is continued to a highly proliferative partial myogenic phenotype.
Methods: We performed a whole-genome expression array and transcriptome deep sequencing to the cell sorted c-kit+/lin-, c-kit+/CD45+ and myogenic cell line populations. Tissue culture derived cells were analyzed using immunostaining, live microscopy and FACS. Lineage tracing was performed with Pax3, Tie2 and Myosin Heavy Chain-cre mice.
Results: CD45+ CPCs expressed a gene profile, which matches that of non-hematopoietic, resident macrophage like cells found in other tissues. Transcriptome comparison demonstrated a significant up-regulation of the neural crest differentiation pathway genes in c-kit+/lin- CPCs and myogenic cell lines. All the CPCs were traced back to Pax3, neural crest marker, activation. During the transdifferentiation from CD45+ CPCs to myogenic cell line, pluripotency pathways were activated suggesting a spontaneous reprogramming process. Myosin Heavy Chain –linage traced CPCs were marker negative, ruling out a cardiomyocyte origin.
Conclusion: Our data suggests that c-kit+/lineage- cells and resident macrophages have a common lineage origin leading to a possibility to resolve some of the current incoherencies in the field of cardiac regeneration. The neural crest differentiation pathway can be activated in these cells during adulthood, possibly in cardiac stress situations, enabling differentiation to cardiac lineage.
