Abstract 5944: Neural Crest Stem Cells Supply Intrinsic Cardiac Adrenergic Cells and Contribute to Reinnervation After Cardiac Transplantation in Mice
Background: Although sympathetic innervation plays a pivotal role to maintain and modulate cardiac function, reinnervation from the recipient rarely occurs in the transplanted heart. We previously reported neural crest stem cells (NCSC) reside in the heart, and can differentiate into neuron, glia, smooth muscle cells and cardiomyocytes. This study was designed to investigate whether NCSC can supply the intrinsic cardiac adrenergic (ICA) cells, and to elucidate the temporal changes and the roles of ICA cells in the transplanted heart.
Methods and Results:
We generated double transgenic mice encoding protein 0-Cre/Floxed-EGFP (P0-EGFP), to map neural crest-derived cell fate. NCSC were marked with EGFP expressed nestin, musashi-1 and p75 nerve growth factor (NGF) receptor. They still existed in all parts of the adult heart.
P0-EGFP mice demonstrated the existence of ICA cells, which were nucleated small round cells demarcated with tyrosine hydroxylase (TH, catecholaminergic marker)-immunopositive cells within ventricles. The ICA cells were present in the adult heart ventricles.
We obtained hearts from P0-EGFP mice, and transplanted them into SCID mice through the abdominal aorta. After 4 weeks, not only the sympathetic nerve fascicles located on the epicardial surface, which originated from the stellate ganglia, but also EGFP-positive nerve fibers that were densely observed mainly at the epicardial ventricular layer completely disappeared, indicating that sympathetic nerves from the upper sympathetic ganglia were completely denervated.
Interestingly however, the number of EGFP-positive cells was markedly increased, and these cells were mainly observed at the endocardial myocardium. Most were round and nucleated, and positive for TH immunostaining. Some of them extended neurites among the sprouting nerves, indicating ICA cells.
TH, EGFP and NGF mRNAs were increased over time after transplantation.
Conclusions: These findings indicated that ICA cells were derived from neural crest, and still functioned as catecholaminergic cells in the adult heart. After the donor hearts were once dennervated, NCSC were increased and differentiated into ICA cells, and then contributed to the reinnervation of the transplanted hearts.