期刊
NATURE BIOTECHNOLOGY
卷 31, 期 1, 页码 54-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.2465
关键词
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资金
- Cedars-Sinai Board of Governors Heart Stem Cell Center
- Heart Rhythm Society fellowship
- Heart and Stroke Foundation of Canada fellowship
- American Heart Association [12SDG9020030]
- NHLBI [1R01HL111646-01A1]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL111646] Funding Source: NIH RePORTER
The heartbeat originates within the sinoatrial node (SAN), a small structure containing <10,000 genuine pacemaker cells. If the SAN fails, the similar to 5 billion working cardiomyocytes downstream of it become quiescent, leading to circulatory collapse in the absence of electronic pacemaker therapy. Here we demonstrate conversion of rodent cardiomyocytes to SAN cells in vitro and in vivo by expression of Tbx18, a gene critical for early SAN specification. Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo, focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells. The creation of induced SAN pacemaker (iSAN) cells opens new prospects for bioengineered pacemakers.
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