ISL1 cardiovascular progenitor cells for cardiac repair after myocardial infarction
Oscar Bartulos, … , Jordan S. Pober, Yibing Qyang
Oscar Bartulos, … , Jordan S. Pober, Yibing Qyang
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e80920. https://doi.org/10.1172/jci.insight.80920.
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Research Article Cardiology Neuroscience Stem cells Transplantation Vascular biology

ISL1 cardiovascular progenitor cells for cardiac repair after myocardial infarction

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.

Authors

Oscar Bartulos, Zhen Wu Zhuang, Yan Huang, Nicole Mikush, Carol Suh, Alda Bregasi, Lin Wang, William Chang, Diane S. Krause, Lawrence H. Young, Jordan S. Pober, Yibing Qyang

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Figure 1

Cardiac differentiation of mouse ISL1 cardiovascular progenitor cell–derived spheroids (mISL1-CPC spheroids).

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Cardiac differentiation of mouse ISL1 cardiovascular progenitor cell–der...
(A) Test for spheroid formation using 96-U wells with (top left) or without (top right) methylcellulose, hanging drops (bottom left), or forced aggregation in 96-V wells (bottom right). Mouse ISL1-CPC spheroids were only formed in 96-U wells, in the presence of methylcellulose (top left, black arrow). Scale bars: 100 μm. (B) Mouse ISL1-CPCs were isolated by FACS and plated as monolayer culture (single cells) or spheroids on Matrigel-coated plates for 1 week. Cells were fixed and stained for cardiac troponin T (cTnT; green). Scale bar: 200 μm. Scale bar for inset pictures: 50 μm. (C) Staining for cTnT (green) in ISL1-CPC spheroids plated on the Matrigel-coated 4-well chamber slide for 6 days. Pictures represent ×20 magnifications (Scale bar: 50 μm) on the left and ×90 magnification (Scale bar: 20 μm) on the right. Note in the ×90 picture the presence of sarcomeric structures. (D) One week after plating on Matrigel, mISL1-CPC single cells or spheroids were subjected to FACS analysis to quantify the percentage of cardiomyocytes marked by the specific cardiac marker cTnT and the early cardiomyocyte marker smooth muscle α-actin (SMA). Quantifications of SMA+ cells and cardiomyocytes (cTnT+/SMA+) from n = 4 independent experiments (unpaired 2-tailed Student’s t test). **P < 0.01. See also Supplemental Figures 1 and 2 and Movies 1 and 2.