Embryonic Stem Cell-Derived CD166+ Precursors Develop Into Fully Functional Sinoatrial-Like Cells

被引：51

作者：

Scavone, Angela ^{[1
]}

Capilupo, Daniela ^{[1
]}

Mazzocchi, Nausicaa ^{[1
,3
]}

Crespi, Alessia ^{[1
]}

Zoia, Stefano ^{[1
]}

Campostrini, Giulia ^{[1
]}

Bucchi, Annalisa ^{[1
]}

Milanesi, Raffaella ^{[1
]}

Baruscotti, Mirko ^{[1
,2
]}

Benedetti, Sara ^{[3
,4
]}

Antonini, Stefania ^{[1
]}

Messina, Graziella ^{[1
]}

DiFrancesco, Dario ^{[1
,2
]}

Barbuti, Andrea ^{[1
,2
]}

机构：

[1] Univ Milan, Dept Biosci, I-20133 Milan, Italy

[2] Univ Milan, Ctr Interuniv Med Mol & Biofis Applicada, I-20133 Milan, Italy

[3] Ist Sci San Raffaele, Div Regenerat Med, I-20132 Milan, Italy

[4] Univ Roma La Sapienza, Dept Histol & Med Embriol, I-00185 Rome, Italy

来源：

CIRCULATION RESEARCH | 2013年 / 113卷 / 04期

关键词：

cardiac progenitor cells; embryonic stem cells; HCN channels; pacemaker; sinoatrial node; CARDIAC PROGENITOR CELLS; MOUSE HEART DEVELOPMENT; CONDUCTION SYSTEM; ELECTROPHYSIOLOGICAL PROPERTIES; ACTION-POTENTIALS; CALCIUM-CHANNELS; PACEMAKER CELLS; SURFACE-MARKER; CA2+ CHANNELS; HCN4; CHANNEL;

D O I：

10.1161/CIRCRESAHA.113.301283

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rationale: A cell-based biological pacemaker is based on the differentiation of stem cells and the selection of a population displaying the molecular and functional properties of native sinoatrial node (SAN) cardiomyocytes. So far, such selection has been hampered by the lack of proper markers. CD166 is specifically but transiently expressed in the mouse heart tube and sinus venosus, the prospective SAN. Objective: We have explored the possibility of using CD166 expression for isolating SAN progenitors from differentiating embryonic stem cells. Methods and Results: We found that in embryonic day 10.5 mouse hearts, CD166 and HCN4, markers of the pacemaker tissue, are coexpressed. Sorting embryonic stem cells for CD166 expression at differentiation day 8 selects a population of pacemaker precursors. CD166(+) cells express high levels of genes involved in SAN development (Tbx18, Tbx3, Isl-1, Shox2) and function (Cx30.2, HCN4, HCN1, CaV1.3) and low levels of ventricular genes (Cx43, Kv4.2, HCN2, Nkx2.5). In culture, CD166(+) cells form an autorhythmic syncytium composed of cells morphologically similar to and with the electrophysiological properties of murine SAN myocytes. Isoproterenol increases (+57%) and acetylcholine decreases (-23%) the beating rate of CD166-selected cells, which express the -adrenergic and muscarinic receptors. In cocultures, CD166-selected cells are able to pace neonatal ventricular myocytes at a rate faster than their own. Furthermore, CD166(+) cells have lost pluripotency genes and do not form teratomas in vivo. Conclusions: We demonstrated for the first time the isolation of a nonteratogenic population of cardiac precursors able to mature and form a fully functional SAN-like tissue.

引用

页码：389 / 398

页数：10

共 51 条

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