Faculty Collaboration Database

Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes. Cell Rep 2023 Apr 25;42(4):112330

Date

04/05/2023

Pubmed ID

37014753

Pubmed Central ID

PMC10545814

DOI

10.1016/j.celrep.2023.112330

Scopus ID

2-s2.0-85151483168 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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.

Author List

Kannan S, Miyamoto M, Zhu R, Lynott M, Guo J, Chen EZ, Colas AR, Lin BL, Kwon C

Author

Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Embryonic Stem Cells
Humans
Induced Pluripotent Stem Cells
Mice
Myocytes, Cardiac
Pluripotent Stem Cells
Transcription Factors