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Cardiac Directed Differentiation Using Small Molecule WNT Modulation at Single-Cell Resolution

49 Pages Posted: 13 Apr 2018 Sneak Peek Status: Published

See all articles by Clayton E. Friedman

Clayton E. Friedman

University of Queensland - Institute for Molecular Bioscience

Quan Nguyen

University of Queensland - Institute for Molecular Bioscience

Samuel W. Lukowski

University of Queensland - Institute for Molecular Bioscience

Abbigail Helfer

University of Queensland - Institute for Molecular Bioscience

Han Sheng Chiu

University of Queensland - Institute for Molecular Bioscience

Holly K. Voges

University of Queensland - Centre for Cardiac and Vascular Biology

Shengbao Suo Suo

Chinese Academy of Sciences (CAS) - Key Laboratory of Computational Biology

Jing-Dong Jackie Han

Chinese Academy of Sciences (CAS) - Key Laboratory of Computational Biology

Pierre Osteil

Children's Medical Research Institute (CMRI) - Embryology Unit

Guangdun Peng

Chinese Academy of Sciences (CAS), Shanghai Institutes for Biological Sciences, Institute of Biochemistry and Cell Biology, State Key Laboratory of Cell Biology

Naihe Jing

Chinese Academy of Sciences (CAS) - Institute of Biochemistry and Cell Biology

Greg J. Baillie

University of Queensland - Institute for Molecular Bioscience

Anne Senabouth

University of Queensland - Institute for Molecular Bioscience

Angelika N. Christ

University of Queensland - Institute for Molecular Bioscience

Timothy J. Bruxner

University of Queensland - Institute for Molecular Bioscience

Charles E. Murry

University of Washington - Department of Pathology

Emily S. Wong

University of Queensland - School Biomedical Science

Jun Ding

Carnegie Mellon University - Computational Biology Department

Yuliang Wang

University of Washington - Department of Pathology

James Hudson

University of Queensland - Centre for Cardiac and Vascular Biology

Ziv Bar-Joseph

Carnegie Mellon University - Computational Biology Department

Patrick P. L. Tam

Children's Medical Research Institute (CMRI) - Embryology Unit

Joseph E. Powell

University of Queensland - Institute for Molecular Bioscience

Nathan J. Palpant

University of Queensland - Institute for Molecular Bioscience

More...

Abstract

Differentiation into diverse cell lineages requires orchestration of gene regulatory networks guiding cell fate choices. Here, we present the dissection of cellular composition and gene networks from transcriptomic data of 43,168 cells across five discrete time points during cardiacdirected differentiation. We utilize unsupervised clustering and implement a lineage trajectory prediction algorithm that integrates transcription factor networks to predict cell fate progression of 15 subpopulations that correlate with germ layer and cardiovascular differentiation in vivo. These data reveal transcriptional networks underlying lineage derivation of mesoderm, definitive endoderm, vascular endothelium, cardiac precursors, and definitive cell types that comprise cardiomyocytes and a previously unrecognized cardiac outflow tract population. Single cell analysis of genetic regulators governing cardiac fate diversification identified the non-DNA binding homeodomain protein, HOPX, as functionally necessary for endothelial specification. Our findings further implicate dysregulation of HOPX during in vitro cardiac-directed differentiation underlying the molecular and physiological immaturity of stem cell-derived cardiomyocytes.

Keywords: human pluripotent stem cells, cardiomyocytes, transcriptomic profiling, outflow tract, heart, development, CRISPR, engineered heart tissue, RNA-sequencing, HOPX, scdiff

Suggested Citation

Friedman, Clayton E. and Nguyen, Quan and Lukowski, Samuel W. and Helfer, Abbigail and Chiu, Han Sheng and Voges, Holly K. and Suo Suo, Shengbao and Jackie Han, Jing-Dong and Osteil, Pierre and Peng, Guangdun and Jing, Naihe and Baillie, Greg J. and Senabouth, Anne and Christ, Angelika N. and Bruxner, Timothy J. and Murry, Charles E. and Wong, Emily S. and Ding, Jun and Wang, Yuliang and Hudson, James and Bar-Joseph, Ziv and Tam, Patrick P. L. and Powell, Joseph E. and Palpant, Nathan J., Cardiac Directed Differentiation Using Small Molecule WNT Modulation at Single-Cell Resolution (2018). Available at SSRN: https://ssrn.com/abstract=3155757 or http://dx.doi.org/10.2139/ssrn.3155757
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Clayton E. Friedman

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Quan Nguyen

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Samuel W. Lukowski

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Abbigail Helfer

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Han Sheng Chiu

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Holly K. Voges

University of Queensland - Centre for Cardiac and Vascular Biology

QLD
Brisbane, Brisbane
Australia

Shengbao Suo Suo

Chinese Academy of Sciences (CAS) - Key Laboratory of Computational Biology

Shanghai
China

Jing-Dong Jackie Han

Chinese Academy of Sciences (CAS) - Key Laboratory of Computational Biology

Shanghai
China

Pierre Osteil

Children's Medical Research Institute (CMRI) - Embryology Unit

Westmead, NSW 2145
Australia

Guangdun Peng

Chinese Academy of Sciences (CAS), Shanghai Institutes for Biological Sciences, Institute of Biochemistry and Cell Biology, State Key Laboratory of Cell Biology

Shanghai
China

Naihe Jing

Chinese Academy of Sciences (CAS) - Institute of Biochemistry and Cell Biology

320 Yue Yang Road
Shanghai, 200031
China

Greg J. Baillie

University of Queensland - Institute for Molecular Bioscience ( email )

St. Lucia
Brisbane
Australia

Anne Senabouth

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Angelika N. Christ

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Timothy J. Bruxner

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Charles E. Murry

University of Washington - Department of Pathology

Seattle, WA
United States

Emily S. Wong

University of Queensland - School Biomedical Science

QLD
Brisbane, 4072
Australia

Jun Ding

Carnegie Mellon University - Computational Biology Department

Pittsburgh, PA 15213
United States

Yuliang Wang

University of Washington - Department of Pathology

Seattle, WA
United States

James Hudson

University of Queensland - Centre for Cardiac and Vascular Biology

QLD
Brisbane, Brisbane
Australia

Ziv Bar-Joseph

Carnegie Mellon University - Computational Biology Department

Pittsburgh, PA 15213
United States

Patrick P. L. Tam

Children's Medical Research Institute (CMRI) - Embryology Unit

Westmead, NSW 2145
Australia

Joseph E. Powell

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

Nathan J. Palpant (Contact Author)

University of Queensland - Institute for Molecular Bioscience

St. Lucia
Brisbane
Australia

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