A cardiomyocyte is a specialized muscle cell responsible for the heart’s contractions that pump blood throughout the body. Cardiomyocyte proliferation is the creation of new heart muscle cells from existing ones. This process is a focus of medical research because it holds the potential to heal hearts damaged by injury or disease by stimulating the organ to replace lost cells and restore function.
The Heart’s Inability to Self-Repair
When the heart sustains an injury, such as a myocardial infarction (heart attack), billions of heart muscle cells can be lost. Unlike some other organs, the adult heart has a very limited capacity to replace these dead or damaged cardiomyocytes. Following an injury, the body’s repair process involves removing the dead cells and replacing them with scar tissue in a process called fibrosis. This scar tissue is primarily made of collagen and is deposited by cells called fibroblasts.
This fibrotic scar tissue lacks the ability to contract and contribute to the heart’s pumping action. While the scar is necessary to maintain the structural integrity of the heart wall and prevent it from rupturing, it is functionally a patch rather than a true repair. Over time, the remaining healthy heart muscle must work harder to compensate for the non-contractile scar, which can lead to a decline in cardiac function and eventually heart failure.
The formation of this permanent scar is why damage from a heart attack is irreversible. The body’s default healing mechanism prioritizes a quick structural fix over functional restoration. This limitation drives the scientific search for methods to encourage the heart to regenerate new muscle instead of forming a scar.
Natural Proliferation Throughout the Lifespan
The heart’s capacity for cardiomyocyte proliferation changes dramatically over a lifetime. During fetal development and immediately after birth, cardiomyocytes divide avidly, a process that allows the heart to grow rapidly. In mammals, this proliferative ability continues for a short window after birth. For instance, studies in mice show that for about the first week of life, their hearts can effectively regenerate after injury.
This window of regenerative potential closes quickly. Soon after birth, cardiomyocytes in mammals largely exit the cell cycle, which is the series of events that leads to cell division. Instead of dividing, the heart muscle cells grow in size, a process known as hypertrophy, to support the body’s growth. In the adult human heart, the rate of cardiomyocyte turnover is extremely low, with estimates suggesting that less than 1% of these cells are replaced annually.
Researchers study the hearts of neonatal mammals to understand the molecular signals and genetic programs active during this proliferative phase. The goal is to identify the natural “on” switches for cell division that are turned “off” in adulthood. Understanding this transition from proliferation to hypertrophy may hold the secret to reawakening the heart’s dormant abilities.
Scientific Approaches to Induce Proliferation
Scientists are exploring several strategies to coax adult cardiomyocytes back into the cell cycle to create new muscle. The cell cycle is controlled by proteins that act as accelerators and brakes. In adult cardiomyocytes, the brakes are permanently engaged, so research focuses on temporarily releasing them by targeting specific regulatory pathways.
Genetic Pathway Manipulation
One target is the Hippo signaling pathway, a natural repressor of cell proliferation. Inactivating components of this pathway in adult mouse hearts can cause cardiomyocytes to re-enter the cell cycle and divide. Another approach involves overexpressing proteins that drive the cell cycle forward, such as cyclins, which has resulted in cardiomyocyte DNA synthesis in animal models.
Growth Factors and Proteins
Specific molecules like growth factors can send external signals that instruct cardiomyocytes to divide. One such molecule is neuregulin-1 (NRG1), which is involved in heart development. When NRG1 binds to its receptor on cardiomyocytes, it can trigger a signaling cascade that promotes proliferation, and administering it to mice after a heart attack has been shown to improve heart function.
MicroRNA Therapies
MicroRNAs are small molecules that regulate gene expression instead of coding for proteins. Certain microRNAs are highly active during fetal heart development but are silenced in adulthood. Reintroducing specific microRNAs into adult cardiomyocytes in animal models has stimulated cell cycle entry, leading to reduced scar size and improved cardiac function after injury.
Hurdles in Regenerative Medicine
A primary challenge in translating these approaches to patients is the risk of uncontrolled cell growth, or cancer. The mechanisms suppressed in adult cardiomyocytes to prevent division also protect against tumor formation. Forcing cells to proliferate carries the risk that the process might not stop, leading to harmful overgrowth.
Another challenge is functional integration. For the heart to benefit, newly generated cardiomyocytes must work as part of a coordinated team. They need to align with existing muscle, establish electrical connections to contract in sync, and mature into strong cells. Without proper integration, new cells could fail to contribute to pumping or create electrical disturbances known as arrhythmias.
Developing a reliable delivery method is another obstacle. The treatment must be delivered specifically to the injured heart tissue to avoid causing cell proliferation in other organs. Researchers are exploring systems like direct injections, specialized patches, and viral vectors designed to target only cardiomyocytes, each with its own challenges in efficiency and safety.