Abstract 1265: Neural Crest Stem Cells Supply Cardiomyocytes For The Physiological Turnover And The Regeneration After Myocardial Infarction
[Introduction] The adult heart contains several multipotent stem cell populations including c-Kit+, Sca-1+, Isl-1+, and side population cells, which have the capacity to differentiate into various cell types including cardiomyocytes. The physiological and pathophysiological roles of these adult stem cell populations remain unclear. Neural crest-derived cells migrate into various tissues and differentiate into a variety of cell types, however some also remain in the adult as stem cells. We previously identified dormant neural crest stem cells (NCSC) in the heart. These cells expressed Nestin, Musashi-1, P75NGFR, and could form spheres. This study investigated whether NCSC supply cardiomyocytes for the physiological turnover and the regeneration after myocardial infarction (MI).
We generated double-transgenic mice by crossing P0-Cre mice with CAG-CAT-EGFP mice, and performed neural crest-derived cell linage analysis.
MI was generated by ligation of the left anterior descending coronary artery in 10-week-old double-Tg mice, and immunofluorescent staining against actinin, GATA4, nestin, P75NGFR, and c-Kit was examined.
In the control heart, EGFP+ cells were observed at the intramuscular and subepicardial layers of both ventricles and atrium. These cells were nestin and P75NGFR positive and some were GATA4 and c-Kit positive. A few cells were EGFP+ cardiomyocytes.
EGFP+ cardiomyocytes were first observed at the ischemic border zone area. They first appeared at 2 weeks after MI, gradually increased, and peaked at 4 weeks.
EGFP+ cardiomyocytes did not increase at the non-infarcted area for the first 4 weeks.
Amazingly, however, they increased after 8 weeks, and were prominent after 16 weeks. Their number at 16 weeks was significantly higher than that of border zone area. These findings indicated that NCSC supplied new cardiomyocytes and contributed to the heart repair after MI, and that new cardiomyocytes were regenerated at the border zone in the early phase, and at the nonischemic area in the late phase to adapt cardiac remodeling. This is the first evidence of a critical role for cardiac stem cells, and in particular NCSC, in the supply of cardiomyocytes under physiological and pathophysiological conditions.