Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes

Suraj Kannan; Matthew Miyamoto; Renjun Zhu; Michaela Lynott; Jason Guo; Elaine Zhelan Chen; Alexandre R. Colas; Brian Leei Lin; Chulan Kwon

Cell Reports (Apr 2023)

Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes

Suraj Kannan,
Matthew Miyamoto,
Renjun Zhu,
Michaela Lynott,
Jason Guo,
Elaine Zhelan Chen,
Alexandre R. Colas,
Brian Leei Lin,
Chulan Kwon

Affiliations

Suraj Kannan: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Matthew Miyamoto: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Renjun Zhu: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Michaela Lynott: Sanford Burham Prebys Medical Discovery Institute, San Diego, CA, USA
Jason Guo: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Elaine Zhelan Chen: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Alexandre R. Colas: Sanford Burham Prebys Medical Discovery Institute, San Diego, CA, USA
Brian Leei Lin: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
Chulan Kwon: Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 4
p. 112330

Abstract

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Summary: A limitation in the application of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) is the failure of these cells to achieve full functional maturity. The mechanisms by which directed differentiation differs from endogenous development, leading to consequent PSC-CM maturation arrest, remain unclear. Here, we generate a single-cell RNA sequencing (scRNA-seq) reference of mouse in vivo CM maturation with extensive sampling of previously difficult-to-isolate perinatal time periods. We subsequently generate isogenic embryonic stem cells to create an in vitro scRNA-seq reference of PSC-CM-directed differentiation. Through trajectory reconstruction, we identify an endogenous perinatal maturation program that is poorly recapitulated in vitro. By comparison with published human datasets, we identify a network of nine transcription factors (TFs) whose targets are consistently dysregulated in PSC-CMs across species. Notably, these TFs are only partially activated in common ex vivo approaches to engineer PSC-CM maturation. Our study can be leveraged toward improving the clinical viability of PSC-CMs.

CP: Stem cell research

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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