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JCI Insight. 2016 Jul 7;1(10). pii: e80920.

ISL1 cardiovascular progenitor cells for cardiac repair after myocardial infarction.

Author information

1
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.; Yale Stem Cell Center, Yale University, New Haven, Connecticut, USA.
2
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
3
Yale Stem Cell Center, Yale University, New Haven, Connecticut, USA.; Department of Laboratory Medicine, Yale University, New Haven, Connecticut, USA.
4
Department of Internal Medicine, Section of Nephrology, Yale University, New Haven, Connecticut, USA.
5
Yale Stem Cell Center, Yale University, New Haven, Connecticut, USA.; Department of Laboratory Medicine, Yale University, New Haven, Connecticut, USA.; Department of Cell Biology, Yale University, New Haven, Connecticut, USA.; Department of Pathology, Yale University, New Haven, Connecticut, USA.
6
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.; Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, USA.
7
Department of Pathology, Yale University, New Haven, Connecticut, USA.; Department of Immunobiology, Yale University, New Haven, Connecticut, USA.; Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut, USA.
8
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.; Yale Stem Cell Center, Yale University, New Haven, Connecticut, USA.; Department of Pathology, Yale University, New Haven, Connecticut, USA.; Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut, USA.

Abstract

Cardiovascular progenitor cells (CPCs) expressing the ISL1-LIM-homeodomain transcription factor contribute developmentally to cardiomyocytes in all 4 chambers of the heart. Here, we show that ISL1-CPCs can be applied to myocardial regeneration following injury. We used a rapid 3D methylcellulose approach to form murine and human ISL1-CPC spheroids that engrafted after myocardial infarction in murine hearts, where they differentiated into cardiomyocytes and endothelial cells, integrating into the myocardium and forming new blood vessels. ISL1-CPC spheroid-treated mice exhibited reduced infarct area and increased blood vessel formation compared with control animals. Moreover, left ventricular (LV) contractile function was significantly better in mice transplanted with ISL1-CPCs 4 weeks after injury than that in control animals. These results provide proof-of-concept of a cardiac repair strategy employing ISL1-CPCs that, based on our previous lineage-tracing studies, are committed to forming heart tissue, in combination with a robust methylcellulose spheroid-based delivery approach.

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