Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair.

Abstract

There are intense interests in discovering proregenerative medicine leads that can promote cardiac differentiation and regeneration, as well as repair damaged heart tissues. We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects. Two related compounds with novel structures, named as Cardiomogen 1 and 2 (CDMG1 and CDMG2), were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population. We find that Cardiomogen acts as a Wnt inhibitor by targeting β-catenin and reducing Tcf/Lef-mediated transcription in cultured cells. CDMG treatment of amputated zebrafish hearts reduces nuclear β-catenin in injured heart tissue, increases cardiomyocyte (CM) proliferation, and expedites wound healing, thus accelerating cardiac muscle regeneration. Importantly, Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial infarction. Injured hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue, which are in part attributable to the β-catenin reduction. Our findings indicate Cardiomogen as a Wnt inhibitor in enhancing injury-induced CM proliferation and heart regeneration, highlighting the values of embryo-based small molecule screens in discovery of effective and safe medicine leads.

• Authors: Shuying Xie, Wenbin Fu, Guangju Yu, Xueli Hu, Kaa Seng Lai, Xiangwen Peng, Yating Zhou, Xuejiao Zhu, Plamen Christov, Leah Sawyer, Terri T Ni, Gary A Sulikowski, Zhongzhou Yang, Ethan Lee, Chunyu Zeng, Wei E Wang, Tao P Zhong
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 12 Issue 1 Pg. 42-54 (01 22 2020) ISSN: 1759-4685 [Electronic] United States
• PMID: 30925593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• Small Molecule Libraries
• Wnt Proteins
• Zebrafish Proteins
• beta Catenin
• ctnnb1 protein, zebrafish

Topics

• Animals
• Animals, Genetically Modified
• Cell Differentiation (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Heart Injuries (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Mouse Embryonic Stem Cells (metabolism)
• Myocardial Infarction (drug therapy)
• Myocytes, Cardiac (metabolism)
• Regenerative Medicine (methods)
• Signal Transduction (drug effects)
• Small Molecule Libraries (pharmacology, therapeutic use)
• Wnt Proteins (antagonists & inhibitors)
• Wnt Signaling Pathway (drug effects)
• Wound Healing (drug effects)
• Zebrafish (embryology)
• Zebrafish Proteins (metabolism)
• beta Catenin (metabolism)