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Published 26 September 2005. doi:10.1083/jcb.200504061
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 7, 1135-1146
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Article

 Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart

Yuichi Tomita1,2, Keisuke Matsumura1,2, Yoshio Wakamatsu4, Yumi Matsuzaki3,5, Isao Shibuya1, Haruko Kawaguchi1, Masaki Ieda1,2, Sachiko Kanakubo4, Takuya Shimazaki3,5, Satoshi Ogawa2, Noriko Osumi4, Hideyuki Okano3,5, and Keiichi Fukuda1

1 Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Department of Internal Medicine
2 Cardiopulmonary Division, Department of Internal Medicine
3 Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
4 Department of Developmental Neurobiology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan
5 Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Correspondence to Keiichi Fukuda: kfukuda{at}sc.itc.keio.ac.jp

Arodent cardiac side population cell fraction formed clonal spheroids in serum-free medium, which expressed nestin, Musashi-1, and multi-drug resistance transporter gene 1, markers of undifferentiated neural precursor cells. These markers were lost following differentiation, and were replaced by the expression of neuron-, glial-, smooth muscle cell–, or cardiomyocyte-specific proteins. Cardiosphere-derived cells transplanted into chick embryos migrated to the truncus arteriosus and cardiac outflow tract and contributed to dorsal root ganglia, spinal nerves, and aortic smooth muscle cells. Lineage studies using double transgenic mice encoding protein 0–Cre/Floxed-EGFP revealed undifferentiated and differentiated neural crest-derived cells in the fetal myocardium. Undifferentiated cells expressed GATA-binding protein 4 and nestin, but not actinin, whereas the differentiated cells were identified as cardiomyocytes. These results suggest that cardiac neural crest-derived cells migrate into the heart, remain there as dormant multipotent stem cells—and under the right conditions—differentiate into cardiomyocytes and typical neural crest-derived cells, including neurons, glia, and smooth muscle.

Abbreviations used in this paper: {alpha}-SMA, {alpha}-smooth muscle actin; Ab, antibody; EYFP, enhanced yellow fluorescent protein; GATA4, GATA-binding protein 4; GFAP, glial fibrillary acidic protein; HNK1, human natural killer-1; MAP2, microtubule-associated protein 2; MASH1, neural-specific helix-loop-helix–type transcription factor; MDR-1, multi-drug resistance transporter gene 1; MHC, myosin heavy chain; atrial natriuretic peptide; MP, main population; MSA, migration staging area; P0, protein 0; PNS, peripheral nervous system; Sca-1, stem cell antigen-1; SP, side population; T{alpha}-1, {alpha}-tubulin promoter; Tg, transgenic.


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