Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic Myocardial Infarction

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:56

Article

Behfar, Atta¹  Yamada, Satsuki¹  Crespo-Diaz, Ruben¹  Nesbitt, Jonathan J.¹  Rowe, Lois A.¹  Perez-Terzic, Carmen^1,2  Gaussin, Vinciane³  Homsy, Christian³  Bartunek, Jozef⁴  Terzic, Andre¹ 

[1] Mayo Clin, Dept Med, Div Cardiovasc Dis, Marriott Heart Dis Res Program, Rochester, MN 55905 USA

[2] Mayo Clin, Dept Phys Med & Rehabil, Rochester, MN 55905 USA

[3] Cardio3 BioSci, Mont St Guibert, Belgium

[4] Onze Lieve Vrouw Hosp, Ctr Cardiovasc, Aalst, Belgium

关键词: cell therapy;    ischemic cardiomyopathy;    heart failure;    patient-derived;    transplantation;   

DOI  :  10.1016/j.jacc.2010.03.066

来源: Elsevier

【 摘 要 】

Objectives The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction. Background Adult stem cells, delivered in their nave state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome. Methods hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1, bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points. Results Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix-loop-helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. Conclusions Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy. (J Am Coll Cardiol 2010; 56: 721-34) (C) 2010 by the American College of Cardiology Foundation

【 授权许可】

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