Abstract 3346: NGF Promotes Neural Crest-Derived Cells to Proliferate and Differentiate Into Intrinsic Cardiac Adrenergic Cells and Contributes to Reinnervation After Myocardial Infarction in Mice
[Background] Fatal arrhythmia is one of the major causes of sudden cardiac death after myocardial infarction (MI), and heterogeneous reinnervation after MI provokes arrhythmogenesis. Despite its importance, little is known about what kind of substrates or chemical factors contribute to the proarrhythmic reinnervation. The present study scrutinized the developmental origin of intrinsic cardiac adrenergic (ICA) cells, and investigated ICA cells which nourish the reinnervation after MI which are modified by nerve growth factor (NGF).
[Methods and Results]
We analyzed double transgenic mice, encoding protein 0-Cre/Floxed-EGFP (P0-EGFP), which could map neural crest-derived cell fate. EGFP positive cells still exist in all parts of the heart after the birth, and some of these cells still hold stem cell characteristics expressing nestin, musashi-1 and p75 nerve growth factor (NGF) receptor, and showing sphere formation.
We also analyzed dopamine beta-hydroxylase-Cre/Floxed-EGFP (DBH-EGFP) mice for mapping catecholaminergic cell fate. Among EGFP positive cells, ICA cells, demarcated with tyrosine hydroxylase (TH, catecholaminergic marker)-immunopositive cells, were present within ventricles; they were nucleated and round-shaped. In P0-EGFP mice, the same characteristic cells existed in the heart co-expressing EGFP.
Sorted residual neural crest derived cells in P0-EGFP neonate heart differentiated into neural cells, expressing TH. The neural cell proliferation and differentiation were enhanced by adding NGF.
ICA cell number and TH mRNA expression within ventricles were increased in transgenic mice overexpressing NGF in the heart.
P0-EGFP mice were subjected to MI by ligating the coronary artery.
EGFP-positive cells were markedly increased concomitant with cardiac NGF upregulation after MI especially in the border zone area. Many of these cells also expressed neural markers and TH.
[Conclusions] These findings demonstrated that neural crest-derived cells could differentiate into ICA cells, although it was dependent on NGF synthesis in the heart. Neural crest-derived cells were mobilized to the infarcted area, and proliferated and differentiated into TH-positive ICA cells, contributing to reinnervation after MI.