Cardiopoietic programming of embryonic stem cells for tumor-free heart repair

被引:176
作者
Behfar, Atta
Perez-Terzic, Carmen
Faustino, Randolph S.
Arrell, D. Kent
Hodgson, Denice M.
Yamada, Satsuki
Puceat, Michel
Niederlander, Nicolas
Alekseev, Alexey E.
Zingman, Leonid V.
Terzic, Andre
机构
[1] Mayo Clin & Mayo Fdn, Marriott Heart Dis Res Program, Div Cardiovasc Dis, Dept Med, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA
[3] Mayo Clin & Mayo Fdn, Dept Med Genet, Rochester, MN 55905 USA
[4] Mayo Clin & Mayo Fdn, Dept Phys Med & Rehabil, Rochester, MN 55905 USA
关键词
D O I
10.1084/jem.20061916
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Embryonic stem cells have the distinct potential for tissue regeneration, including cardiac repair. Their propensity for multilineage differentiation carries, however, the liability of neoplastic growth, impeding therapeutic application. Here, the tumorigenic threat associated with embryonic stem cell transplantation was suppressed by cardiac-restricted transgenic expression of the reprogramming cytokine TNF-alpha, enhancing the cardiogenic competence of recipient heart. The in vivo aptitude of TNF-alpha to promote cardiac differentiation was recapitulated in embryoid bodies in vitro. The procardiogenic action required an intact endoderm and was mediated by secreted cardio-inductive signals. Resolved TNF alpha-induced endoderm-derived factors, combined in a cocktail, secured guided differentiation of embryonic stem cells in monolayers produce cardiac progenitors termed cardiopoietic cells. Characterized by a down-regulation of oncogenic markers, up-regulation, and nuclear translocation of cardiac transcription factors, this predetermined population yielded functional cardiomyocyte progeny. Recruited cardiopoietic cells delivered in infarcted hearts generated cardiomyocytes that proliferated into scar tissue, integrating with host myocardium for tumor-free repair. Thus, cardiopoietic programming establishes a strategy to hone stem cell pluripotency, offering a tumor-resistant approach for regeneration.
引用
收藏
页码:405 / 420
页数:16
相关论文
共 79 条
[21]   NK-2 homeobox genes and heart development [J].
Harvey, RP .
DEVELOPMENTAL BIOLOGY, 1996, 178 (02) :203-216
[22]   An overview and synopsis of techniques for directing stem cell differentiation in vitro [J].
Heng, BC ;
Cao, T ;
Haider, HK ;
Wang, DZM ;
Sim, EKW ;
Ng, SC .
CELL AND TISSUE RESEARCH, 2004, 315 (03) :291-303
[23]   Stable benefit of embryonic stem cell therapy in myocardial infarction [J].
Hodgson, DM ;
Behfar, A ;
Zingman, LV ;
Kane, GC ;
Perez-Terzic, C ;
Alekseev, AE ;
Pucéat, M ;
Terzic, A .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2004, 287 (02) :H471-H479
[24]   Cellular remodeling in heart failure disrupts KATP channel-dependent stress tolerance [J].
Hodgson, DM ;
Zingman, LV ;
Kane, GC ;
Perez-Terzic, C ;
Bienengraeber, M ;
Ozcan, C ;
Gumina, RJ ;
Pucar, D ;
O'Coclain, F ;
Mann, DL ;
Alekseev, AE ;
Terzic, A .
EMBO JOURNAL, 2003, 22 (08) :1732-1742
[25]   Tissue expression and immunolocalization of tumor necrosis factor-α in postinfarction dysfunctional myocardium [J].
Irwin, MW ;
Mak, S ;
Mann, DL ;
Qu, R ;
Penninger, JM ;
Yan, A ;
Dawood, F ;
Wen, WH ;
Shou, ZP ;
Liu, P .
CIRCULATION, 1999, 99 (11) :1492-1498
[26]   KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension [J].
Kane, Garvan C. ;
Behfar, Atta ;
Dyer, Roy B. ;
O'Cochlain, D. Fearghas ;
Liu, Xiao-Ke ;
Hodgson, Denice M. ;
Reyes, Santiago ;
Miki, Takashi ;
Seino, Susumu ;
Terzic, Andre .
HUMAN MOLECULAR GENETICS, 2006, 15 (15) :2285-2297
[27]   Efficient cardiomyogenic differentiation of embryonic stem cell by fibroblast growth factor 2 and bone morphogenetic protein 2 [J].
Kawai, T ;
Takahashi, T ;
Esaki, M ;
Ushikoshi, H ;
Nagano, S ;
Fujiwara, H ;
Kosai, K .
CIRCULATION JOURNAL, 2004, 68 (07) :691-702
[28]   Electromechanical integration of cardiomyocytes derived from human embryonic stem cells [J].
Kehat, I ;
Khimovich, L ;
Caspi, O ;
Gepstein, A ;
Shofti, R ;
Arbel, G ;
Huber, I ;
Satin, J ;
Itskovitz-Eldor, J ;
Gepstein, L .
NATURE BIOTECHNOLOGY, 2004, 22 (10) :1282-1289
[29]   Increased TNF-α and decreased TGF-β expression in peripheral blood leukocytes after acute myocardial infarction [J].
Kempf, K ;
Haltern, G ;
Füth, R ;
Herder, C ;
Müller-Scholze, S ;
Gülker, H ;
Martin, S .
HORMONE AND METABOLIC RESEARCH, 2006, 38 (05) :346-351
[30]   Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure [J].
Kittleson, MM ;
Minhas, KM ;
Irizarry, RA ;
Ye, SQ ;
Edness, G ;
Breton, E ;
Conte, JV ;
Tomaselli, G ;
Garcia, JGN ;
Hare, JM .
PHYSIOLOGICAL GENOMICS, 2005, 21 (03) :299-307