Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes
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,...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723003418 |
| _version_ | 1797853016926191616 |
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| author | Suraj Kannan Matthew Miyamoto Renjun Zhu Michaela Lynott Jason Guo Elaine Zhelan Chen Alexandre R. Colas Brian Leei Lin Chulan Kwon |
| author_facet | Suraj Kannan Matthew Miyamoto Renjun Zhu Michaela Lynott Jason Guo Elaine Zhelan Chen Alexandre R. Colas Brian Leei Lin Chulan Kwon |
| author_sort | Suraj Kannan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T19:42:33Z |
| format | Article |
| id | doaj.art-d92eadf8c9ae407a8716be839d22c04c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T19:42:33Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d92eadf8c9ae407a8716be839d22c04c2023-04-04T04:08:41ZengElsevierCell Reports2211-12472023-04-01424112330Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytesSuraj Kannan0Matthew Miyamoto1Renjun Zhu2Michaela Lynott3Jason Guo4Elaine Zhelan Chen5Alexandre R. Colas6Brian Leei Lin7Chulan Kwon8Division 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, USADivision 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, USADivision 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, USASanford Burham Prebys Medical Discovery Institute, San Diego, CA, USADivision 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, USADivision 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, USASanford Burham Prebys Medical Discovery Institute, San Diego, CA, USADivision of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USADivision 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723003418CP: Stem cell research |
| spellingShingle | Suraj Kannan Matthew Miyamoto Renjun Zhu Michaela Lynott Jason Guo Elaine Zhelan Chen Alexandre R. Colas Brian Leei Lin Chulan Kwon Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes Cell Reports CP: Stem cell research |
| title | Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes |
| title_full | Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes |
| title_fullStr | Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes |
| title_full_unstemmed | Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes |
| title_short | Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes |
| title_sort | trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell derived cardiomyocytes |
| topic | CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723003418 |
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