An estimated 17.9 million people die from cardiovascular disease yearly, making it the leading cause of death worldwide. During cardiovascular injury, heart muscle cells—or cardiomyocytes—die and are not replaced, thereby impairing overall cardiac function.
“Only one to two percent of mature cardiomyocytes were found to be proliferative in a person’s lifetime,” said Soh Boon Seng at the Institute of Molecular and Cell Biology (IMCB).
Seeking to preserve or restore cardiac function post-injury, scientists have been exploring ways to improve the efficiency of cardiomyocyte cell division, otherwise known as cell proliferation. Soh’s team has now discovered a pathway that reactivates proliferation in mature cardiomyocytes.
The researchers obtained cardiomyocytes from adult mice, as well as derived terminally-differentiated cardiomyocytes from human embryonic stem cells. Typically, as cells become more differentiated, they lose their capacity to proliferate. However, when the researchers activated the Wnt signaling pathway—a molecular pathway regulating embryonic heart development—in terminally-differentiated cardiomyocytes, the cardiomyocytes became ‘dedifferentiated’ and capable of cell division once more.
Importantly, Soh’s team demonstrated two ways to trigger Wnt signaling—using an antibody, or a small molecule called CHIR99021.
“The antibody binds to N-cadherin, a molecule found on the surface of cardiomyocytes, resulting in the release of proteins known as β-catenin from the cell membrane, which in turn activates Wnt signaling,” Soh explained. “Meanwhile, CHIR99021 prevents β-catenin degradation, which achieves the same effect as activating Wnt signaling.”
Unlike the antibody against N-cadherin, which could cause cardiomyocytes to lose their cell-cell contacts, CHIR99021 does not directly interfere with cell-cell adhesion, which makes it more feasible as a therapeutic for heart repair and regeneration. Nonetheless, Soh’s team noted that CHIR99021 alone could not restore proliferation for injured cardiomyocytes.
“Some of the injured cardiomyocytes may have commenced the process of programmed cell death and thus will not respond to CHIR99021 or up-regulation of Wnt signaling. Therefore, we suggest the use of CHIR99021, in combination with another drug such as simvastatin, to inhibit apoptosis and promote Wnt signaling to achieve tissue regeneration,” said Soh.
The team is also looking to use nanoparticles to deliver such drugs specifically, and in a controlled manner, to cardiomyocytes.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).