YAP/TEAD3 signal mediates cardiac lineage commitment of human-induced pluripotent stem cells
Zhenbo Han1, Ying Yu1, Benzhi Cai1
1The Key Laboratory of Cardiovascular Research, Ministry of Education, Department of Pharmacology at College of Pharmacy, Department of Pharmacy at the Affiliated Second Hospital, Harbin Medical University, Harbin, China.
Insights
The Hippo-YAP pathway, specifically YAP-TEAD3 signaling, is crucial for guiding human-induced pluripotent stem cells (hiPSCs) to become cardiomyocytes. Inhibiting YAP disrupts this cardiac differentiation process, offering new therapeutic insights.
Area of Science:
- Stem cell biology
- Cardiovascular research
- Molecular signaling pathways
Background:
- Human-induced pluripotent stem cells (hiPSCs) are a promising source for cardiac cell therapy.
- The precise mechanisms governing hiPSC cardiac differentiation remain incompletely understood.
- The Hippo-YAP signaling pathway is recognized for its role in cell differentiation and organ development.
Purpose of the Study:
- To investigate the role of the Hippo-YAP signaling pathway in the cardiac differentiation of hiPSCs.
- To elucidate the molecular mechanisms by which YAP influences cardiovascular lineage commitment.
Main Methods:
- Treatment of hiPSCs with verteporfin, a YAP inhibitor, during cardiac differentiation.
- Analysis of cellular differentiation stages, including mesoderm cells (MESs) and cardiovascular progenitor cells (CVPCs).
- Investigating the interaction between YAP and TEAD3 using RNA interference (RNAi) to silence TEAD3 expression.
Main Results:
- Verteporfin treatment significantly inhibited hiPSC cardiac differentiation, causing cells to remain at or dedifferentiate to the CVPC stage.
- YAP was found to interact with TEAD3, playing a critical role during the CVPC stage of differentiation.
- Silencing TEAD3 phenocopied the effects of YAP inhibition, confirming its involvement in the process.
Conclusions:
- YAP-TEAD3 signaling is essential for successful cardiomyocyte differentiation from hiPSCs.
- This study provides novel insights into the function of the Hippo-YAP pathway in cardiovascular lineage commitment.
- Findings may inform future strategies for cardiac regenerative medicine using hiPSC-derived cardiomyocytes.
Abstract:
Cardiomyocytes differentiated from human-induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo-YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo-YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage. Consistently, RNAi-based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP-TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo-YAP signal in cardiovascular lineage commitment.
Related Concept Videos
01:21Lineage Commitment
01:13Induced Pluripotent Stem Cells
01:06Induced Pluripotent Stem Cells
Somatic...