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Cell type determination for cardiac differentiation occurs soon after seeding of human induced pluripotent stem cells

Connie L. Jiang, Yogesh Goyal, Naveen Jain, Qiaohong Wang, Rachel E. Truitt, Allison J. Coté, Benjamin Emert, View ORCID ProfileIan A. Mellis, Karun Kiani, Wenli Yang, Rajan Jain, Arjun Raj
doi: https://doi.org/10.1101/2021.08.08.455532
Connie L. Jiang
1Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Yogesh Goyal
2Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
3Center for Synthetic Biology, Northwestern University, Evanston, IL, USA
4Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
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Naveen Jain
1Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Qiaohong Wang
5Department of Medicine, University of Pennsylvania, Philadelphia, PA
6Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA
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Rachel E. Truitt
5Department of Medicine, University of Pennsylvania, Philadelphia, PA
7Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
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Allison J. Coté
8Cell Biology, Physiology, and Metabolism, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Benjamin Emert
9Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Ian A. Mellis
9Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • ORCID record for Ian A. Mellis
Karun Kiani
1Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Wenli Yang
5Department of Medicine, University of Pennsylvania, Philadelphia, PA
7Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
10Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Rajan Jain
5Department of Medicine, University of Pennsylvania, Philadelphia, PA
6Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA
7Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
10Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Arjun Raj
4Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
11Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • For correspondence: arjunrajlab@gmail.com
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Abstract

Cardiac directed differentiation of human induced pluripotent stem cells consistently produces a mixed population of cardiomyocytes and non-cardiac cell types even when using very well-characterized protocols. We wondered whether differentiated cell types might result from intrinsic differences in hiPS cells prior to the onset of differentiation. By associating individual differentiated cells that share a common hiPS cell precursor, we were able to test whether expression variability in differentiated cells was pre-determined from the hiPS cell state. Although within a single experiment, differentiated cells that share an hiPS cell progenitor were more transcriptionally similar to each other than to other cells in the differentiated population, when the same hiPS cells were differentiated in parallel, we did not observe high transcriptional similarity across differentiations. Additionally, we found that substantial cell death occurred during differentiation in a manner that suggested that all cells were equally likely to survive or die, suggesting that there was no intrinsic selection bias for cells descended from particular hiPS cell progenitors. These results led us to wonder about how cells grow out spatially during the directed differentiation process. Labeling cells by their expression of a few canonical cell type marker genes, we showed that cells expressing the same marker tended to occur in patches observable by visual inspection, suggesting that cell type determination across multiple cell types, once initiated, is maintained in a cell-autonomous manner for multiple divisions. Altogether, our results show that while there is substantial heterogeneity in the initial hiPS cell population, that heterogeneity is not responsible for heterogeneous outcomes, and that the window during which cell type specification occurs is likely to begin shortly after the seeding of hiPS cells for differentiation.

Competing Interest Statement

AR receives royalties related to Stellaris RNA FISH probes. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Cell type determination for cardiac differentiation occurs soon after seeding of human induced pluripotent stem cells
Connie L. Jiang, Yogesh Goyal, Naveen Jain, Qiaohong Wang, Rachel E. Truitt, Allison J. Coté, Benjamin Emert, Ian A. Mellis, Karun Kiani, Wenli Yang, Rajan Jain, Arjun Raj
bioRxiv 2021.08.08.455532; doi: https://doi.org/10.1101/2021.08.08.455532
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Cell type determination for cardiac differentiation occurs soon after seeding of human induced pluripotent stem cells
Connie L. Jiang, Yogesh Goyal, Naveen Jain, Qiaohong Wang, Rachel E. Truitt, Allison J. Coté, Benjamin Emert, Ian A. Mellis, Karun Kiani, Wenli Yang, Rajan Jain, Arjun Raj
bioRxiv 2021.08.08.455532; doi: https://doi.org/10.1101/2021.08.08.455532

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