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Updated: Jul 7, 2025
Protein Isolation from the Developing Embryonic Mouse Heart Valve Region
Published on: September 23, 2014
Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair
Lijuan Pei1, Zhaohui Ouyang1, Hongjie Zhang1
1School of Life Sciences and Technology, Institute for Regenerative Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Tongji University, 1239 Siping Road, Shanghai, 200092, China.
Insights
Very-low-density-lipoprotein receptor (Vldlr) signaling suppresses cardiomyocyte proliferation, hindering heart repair. Targeting this pathway may improve cardiac regeneration after injury.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Molecular Signaling
Background:
- Adult cardiomyocytes exhibit limited regenerative capacity post-injury, impacting heart repair.
- Extracellular signals suppressing cardiomyocyte proliferation remain largely unknown.
- Understanding these signals is crucial for developing cardiac regeneration therapies.
Purpose of the Study:
- To identify extracellular signals regulating cardiomyocyte cell cycle.
- To elucidate the role of very-low-density-lipoprotein receptor (Vldlr) in cardiomyocyte proliferation.
- To investigate the impact of Vldlr signaling on cardiac regeneration.
Main Methods:
- Profiling of receptors in postnatal cardiomyocytes.
- Investigating the effects of Vldlr ligands (Reelin and Thrombospondin1) on cardiomyocyte proliferation.
- Utilizing genetic mouse models with targeted gene deletions (Reln, Thbs1, Vldlr) and myocardial infarction.
- Analyzing downstream signaling pathways including Rac1 and Yap.
Main Results:
- Vldlr inhibits neonatal cardiomyocyte cell cycle proliferation.
- Reelin promotes proliferation, while Thrombospondin1 (TSP-1) inhibits it via Vldlr.
- TSP-1/Vldlr signaling regulates cardiomyocyte cell cycle through Rac1 and Yap.
- Genetic disruption of Vldlr or TSP-1 enhances cardiomyocyte proliferation and cardiac repair.
- Reln deficiency impairs neonatal cardiomyocyte proliferation and regeneration.
Conclusions:
- Vldlr integrates extracellular signals to control cardiomyocyte cell cycle and survival.
- The suppressive TSP-1-Vldlr axis contributes to the limited cardiac repair capacity in adult mammals.
- Targeting Vldlr signaling presents a potential therapeutic strategy for enhancing cardiac regeneration.
Abstract:
Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.
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