Research - Repair the Heart

Overview

Heart disease remains a leading global cause of death. The heart muscle cells (cardiomyocytes) constantly contract, which is essential for the heart to pump blood around the body. After an injury, such as a heart attack, millions of cardiomyocytes (CMs) are lost and cannot be innately restored due to the limited self-renewal ability. As a result, the heart remains unrepaired, forming scars (cardiac fibrosis), and undergoes progressive cardiac remodeling, which distorts the heart's structure and diminishes its function. These findings pose significant challenges in the treatment of heart failure. The Liu lab focuses on understanding the molecular mechanism underlying CM proliferation and fibrosis in cardiac remodeling and regeneration. Learn about our current projects: 

1. Investigate the Mechanism Driving CM Dedifferentiation and Proliferation

Reactivating cardiomyocyte (CM) proliferation holds promise for heart regeneration. However, post-natal mammalian CMs develop a compact cytoskeleton crucial for contraction but inhibitory to cell division (cytokinesis). CMs undergoing cytokinesis exhibit sarcomere breakdown, highlighting the necessity of overcoming this structural barrier for therapeutic CM division. This aligns with studies demonstrating that factors like YAP, NRG1/ErbB4, and Yamanaka factors induce CM dedifferentiation and sarcomere breakdown in proliferating CMs. To develop novel therapies for myocardial infarction and heart failure, we aim to elucidate the molecular regulation of cytoskeletal structures, including sarcomeres and microtubules, during CM maturation, dedifferentiation, and proliferation.

2. Investigating Protein Synthesis and Trafficking in Cardiomyocytes

Protein synthesis, degradation, and distribution are fundamental to cardiomyocyte function. While mRNA levels provide valuable information, understanding protein dynamics is crucial. To this end, we've developed a mouse model that allows for the labeling and tracking of newly synthesized proteins in cardiomyocytes. This model will enable us to characterize proteomic profiles and protein trafficking at different developmental stages and injury conditions. By studying these proteome dynamics, we aim to identify potential therapeutic targets for cardiovascular diseases. This research will contribute to a deeper understanding of cardiomyocyte biology and inform the development of novel treatment strategies.

3. Noncanonical Wnt Signaling in Heart Regenerative Repair

In addition to productive cardiomyocyte proliferation during heart regeneration, cardiac fibrosis resolution allows for the recovery of heart pump function. My study has demonstrated that YAP directly regulates the Wls gene in cardiac regeneration. We revealed that (1) Wls-mediated noncanonical Wnt signaling is essential for communication between CMs and cardiac fibroblasts (CFs), and (2) CM-specific noncanonical Wnt ligands suppress CF activation and fibrosis during neonatal heart regeneration (Liu et al. Circ Res. 2021). We also observed that the expression of Wnt receptors is significantly higher in CFs than in other cell types, suggesting that Wnt signaling is tightly regulated in CFs. Bioinformatic analyses of 41 datasets comprising 234 mouse heart samples uncovered injury-response Wnt genes in different cardiac cells and revealed that the expression of noncanonical Wnt genes is significantly increased after MI. We investigate how these secreted Wnt proteins regulate cell-to-cell communication and fibrosis after an injury.