Tissue kallikrein-modified mesenchymal stem cells provide enhanced protection against ischemic cardiac injury after myocardial infarction.

Abstract

BACKGROUND:

Genetically modified mesenchymal stem cells (MSCs) are a promising approach to the treatment of cardiac injury after myocardial infarction (MI).

METHODS AND RESULTS:

Rat MSCs were transduced with adenovirus containing human tissue kallikrein (TK) gene (TK-MSCs), and they secreted human TK into culture medium. Cultured TK-MSCs were more resistant to hypoxia-induced apoptosis and exhibited reduced caspase-3 activity compared to control GFP-MSCs. The effect of TK-MSC injection on cardiac injury was evaluated in rats at 1 and 14 days after MI. At 1 day after MI, human TK expression in the myocardium was associated with improved cardiac function and decreased inflammatory cell accumulation, proinflammatory gene expression and apoptosis. The beneficial effect of TK-MSCs against apoptosis was verified in cultured cardiomyocytes, as TK-MSC-conditioned medium suppressed hypoxia-induced apoptosis and caspase-3 activity, and increased Akt phosphorylation. At 2 weeks after MI, TK-MSCs improved cardiac function, decreased infarct size, attenuated cardiac remodeling, and promoted neovascularization, as compared to GFP-MSCs. Furthermore, the TK-MSC-conditioned medium, containing elevated vascular endothelial growth factor levels, stimulated the proliferation, migration and tube formation of cultured human endothelial cells.

CONCLUSIONS:

Our results indicate that TK-modified MSCs provide enhanced protection against cardiac injury, apoptosis and inflammation, and promote neovascularization after MI, leading to cardiac function improvement.

• Authors: Lin Gao, Grant Bledsoe, Hang Yin, Bo Shen, Lee Chao, Julie Chao
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 77 Issue 8 Pg. 2134-44 ( 2013) ISSN: 1347-4820 [Electronic] Japan
• PMID: 23697984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Tissue Kallikreins
• Casp3 protein, rat
• Caspase 3

Topics

• Adenoviridae
• Animals
• Apoptosis (genetics)
• Caspase 3 (genetics, metabolism)
• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism, pathology)
• Myocardial Infarction (complications, genetics, metabolism, physiopathology, therapy)
• Myocardial Ischemia (etiology, metabolism, pathology, physiopathology, prevention & control)
• Neovascularization, Physiologic
• Rats
• Rats, Sprague-Dawley
• Tissue Kallikreins (biosynthesis, genetics)
• Transduction, Genetic