Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-07333-4
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Funding
- Canadian Institute of Health Research [201210MFE-289547]
- National Institutes of Health [1K99HL128906]
- NIH Progenitor Cell Biology Consortium [PCBC_JS_2013/3_03]
- NIH [R01 HL141851, R01 HL141371, R01 HL130020, R01 HL123968, HL128170]
- CIRM [TRAN4-09884]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL128170, R01HL141371, K99HL128906, R01HL123968, R01HL141851, R00HL128906, R01HL130020] Funding Source: NIH RePORTER
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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity.
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