Delayed enrichment for c-kit and inducing cardiac differentiation attenuated protective effects of BMSCs' transplantation in pig model of acute myocardial ischemia.

Abstract

OBJECTIVE:

To investigate the effects of immature cardiomyocytes differentiated from c-kit(+) bone marrow mesenchymal stem cells (BMSCs) against acute myocardial infarction (AMI).

METHODS:

Miniswine passage 8 BMSCs were enriched for c-kit and induced by 5 μM 5-azacytidine (AZA) for 14 days, and a second enrichment for the dihydropyridine receptor subunit α2δ1 was performed (enriched BMSCs). Thereafter, enriched BMSCs were analyzed by determining cardiac differentiation, secretion function, and the effects of these secreted factors on cardiac stem cells (CSCs). Miniswine with AMI were divided into control, primary BMSCs' (PB), and enriched BMSCs' (EB) groups. Autologous BMSCs were intramyocardially injected into the ischemic regions in PB and EB groups. The following indices were evaluated at different time points, including paracrine of implanted BMSCs, histological and morphological analysis, myocardial perfusion, and cardiac function.

RESULTS:

As shown by in vitro study, enrichment + AZA significantly promoted BMSCs to express cardiac-specific markers and format action potential, but down-regulated the expression of VEGF and bFGF, consequently attenuated BMSCs-inducing CSCs proliferation, migration, and differentiation. The in vivo experiments revealed similar results like the in vitro 6 weeks postoperatively. And in EB group, there were decreased angiogenesis and myocardial perfusion, attenuated resident CSCs-mediated myocardial regeneration, and consequently impaired cardiac function compared with PB group.

CONCLUSIONS:

This pretreatment promoted BMSCs to differentiate into myocardiocytes both in vitro and in vivo, but impaired their paracrine function and effects on resident CSCs, suggesting that inducing cardiac differentiation alone may not improve protective effects of BMSCs transplantation on AMI.

• Authors: Guang-Wei Zhang, Tian-Xiang Gu, Xiao-Yu Guan, Xue-Jun Sun, Da-Qing Jiang, Rui Tang, Xun Qi, Xue-Yuan Li
• Journal: Cardiovascular therapeutics (Cardiovasc Ther) Vol. 33 Issue 4 Pg. 184-92 (Aug 2015) ISSN: 1755-5922 [Electronic] England
• PMID: 25959676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons Ltd.

Chemical References

• Calcium Channels, L-Type
• Vascular Endothelial Growth Factor A
• von Willebrand Factor
• Fibroblast Growth Factor 2
• Proto-Oncogene Proteins c-kit
• Azacitidine

Topics

• Animals
• Azacitidine (pharmacology)
• Calcium Channels, L-Type (metabolism)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Coronary Circulation
• Disease Models, Animal
• Fibroblast Growth Factor 2 (metabolism)
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (drug effects, metabolism)
• Myocardial Infarction (metabolism, pathology, physiopathology, surgery)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology, transplantation)
• Neovascularization, Physiologic
• Paracrine Communication
• Phenotype
• Proto-Oncogene Proteins c-kit (metabolism)
• Regeneration
• Swine
• Swine, Miniature
• Time Factors
• Vascular Endothelial Growth Factor A (metabolism)
• Ventricular Function, Left
• von Willebrand Factor (metabolism)