PGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B2

Murphy, Sheldon D.; Miyamoto, Matthew; Kervadec, Anaïs; Kannan, Suraj; Tampakakis, Emmanouil; Kambhampati, Sandeep; Lin, Brian L.; Paek, Sam; Andersen, Peter; Lee, Dong Ik; Zhu, Renjun; An, Steven S.; Kass, David A.; Uosaki, Hideki; Colas, Alexandre R.; Kwon, Chulan

doi:10.1038/s41467-021-21957-z

Cited by 65 publications

(68 citation statements)

References 62 publications

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“…Dimensionality reduction of our reference with uniform manifold approximation and projection (UMAP) revealed a continuum of maturation from e14 in p56, in concordance with previous results from our group and others [33][34][35] (Fig 1B). As an initial strategy, we considered quantification of maturation status by integration of query datasets with our reference.…”

Section: Scrna-seq CM Reference Captures Maturation-related Changessupporting

confidence: 92%

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Transcriptomic entropy benchmarks stem cell-derived cardiomyocyte maturation against endogenous tissue at single cell level

et al. 2021

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The immaturity of pluripotent stem cell (PSC)-derived tissues has emerged as a universal problem for their biomedical applications. While efforts have been made to generate adult-like cells from PSCs, direct benchmarking of PSC-derived tissues against in vivo development has not been established. Thus, maturation status is often assessed on an ad-hoc basis. Single cell RNA-sequencing (scRNA-seq) offers a promising solution, though cross-study comparison is limited by dataset-specific batch effects. Here, we developed a novel approach to quantify PSC-derived cardiomyocyte (CM) maturation through transcriptomic entropy. Transcriptomic entropy is robust across datasets regardless of differences in isolation protocols, library preparation, and other potential batch effects. With this new model, we analyzed over 45 scRNA-seq datasets and over 52,000 CMs, and established a cross-study, cross-species CM maturation reference. This reference enabled us to directly compare PSC-CMs with the in vivo developmental trajectory and thereby to quantify PSC-CM maturation status. We further found that our entropy-based approach can be used for other cell types, including pancreatic beta cells and hepatocytes. Our study presents a biologically relevant and interpretable metric for quantifying PSC-derived tissue maturation, and is extensible to numerous tissue engineering contexts.

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Section: Scrna-seq CM Reference Captures Maturation-related Changessupporting

confidence: 92%

“…At the single cell level, CM maturation proceeds heterogeneously along a unidirectional trajectory [33]. We were therefore curious to know the extent to which entropy score could capture single cell positioning along this trajectory, in effect functioning as a pseudotime metric.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Transcriptomic entropy benchmarks stem cell-derived cardiomyocyte maturation against endogenous tissue at single cell level

et al. 2021

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“…In addition, ZLN005 treatment increased cell sarcomere length, improved cell calcium handling, and enhanced intercellular connectivity [ 128 ]. Single-cell gene network analysis showed that PGC-1 drives CM maturation via YAP1 and SF3B2 [ 129 ]. All these data indicate that PGC-1 plays as a multifaceted regulator coordinating cellular hypertrophy, contractility, and metabolism of CMs from immature to mature.…”

Section: Mitochondrial Biogenesis and Cardiac Maturationmentioning

confidence: 99%

Mitochondrial Biogenesis, Mitochondrial Dynamics, and Mitophagy in the Maturation of Cardiomyocytes

Ding

Tsang

2021

Cells

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Pluripotent stem cells (PSCs) can undergo unlimited self-renewal and can differentiate into all the cell types present in our body, including cardiomyocytes. Therefore, PSCs can be an excellent source of cardiomyocytes for future regenerative medicine and medical research studies. However, cardiomyocytes obtained from PSC differentiation culture are regarded as immature structurally, electrophysiologically, metabolically, and functionally. Mitochondria are organelles responsible for various cellular functions such as energy metabolism, different catabolic and anabolic processes, calcium fluxes, and various signaling pathways. Cells can respond to cellular needs to increase the mitochondrial mass by mitochondrial biogenesis. On the other hand, cells can also degrade mitochondria through mitophagy. Mitochondria are also dynamic organelles that undergo continuous fusion and fission events. In this review, we aim to summarize previous findings on the changes of mitochondrial biogenesis, mitophagy, and mitochondrial dynamics during the maturation of cardiomyocytes. In addition, we intend to summarize whether changes in these processes would affect the maturation of cardiomyocytes. Lastly, we aim to discuss unanswered questions in the field and to provide insights for the possible strategies of enhancing the maturation of PSC-derived cardiomyocytes.

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“…However, mechanistic data confirming the central role of PPARα in perinatal cardiac adaptation are lacking, and further research is needed to determine if PPARα is the only nutrient-sensing effector in this process. Murphy et al recently showed that regulatory networks driven by PPARα through peroxisome proliferator-activated receptor coactivator-1 (Pgc1α) promote the maturation of pluripotent stem cell-derived cardiomyocytes by regulating YAP1 and SF3B2 proteins [133]. During the fetal-to-neonatal transition, neonatal cardiomyocytes progressively lose their ability to proliferate and enter a hypertrophic phase.…”

Section: Pparαmentioning

confidence: 99%

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

Paredes¹,

Santos-Clemente²,

Ricote³

2021

IJMS

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The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.

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PGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B2

Cited by 65 publications

References 62 publications

Transcriptomic entropy benchmarks stem cell-derived cardiomyocyte maturation against endogenous tissue at single cell level

Transcriptomic entropy benchmarks stem cell-derived cardiomyocyte maturation against endogenous tissue at single cell level

Mitochondrial Biogenesis, Mitochondrial Dynamics, and Mitophagy in the Maturation of Cardiomyocytes

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

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