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Cardiac Tissue Engineering: A Path to Regeneration After Myocardial Infarction

  • Writer: Sophia Yang
    Sophia Yang
  • 4 days ago
  • 9 min read

Every 40 seconds, an American experiences a myocardial infarction (MI), commonly known as a heart attack (Martin et al., 2024). This alarming frequency results in approximately 805,000 Americans suffering from MI annually, with 200,000 of these cases being recurrent events. As one of the most prevalent cardiovascular emergencies in the United States, it represents a significant public health concern. Given the high incidence and recurrence rate of heart attacks—approximately 25% likely to reoccur—the introduction of new treatments for this medical emergency is a critical advancement in medicine. In this paper, different methods for tissue regeneration as potential therapeutic strategies for myocardial infarction will be explored. 


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Understanding Myocardial Infarction

A MI occurs due to the blockage of the coronary artery, which supplies the heart itself with blood. The blockage is created by a blood clot, specifically known as an arterial thrombosis, which is caused by the build-up (atherosclerosis) and rupture of plaque—deposits of cholesterol and other fatty substances—in the artery walls (Mayo Clinic Staff, 2023; Health Direct, 2023). The lack of blood flow results in the deprivation of essential nutrients and oxygen in the cardiomyocytes, or the muscle cells of the heart.. As a result, during a heart attack, a patient undergoes a process called necrosis, the uncontrolled death of body tissue cells (Cleveland Clinic, n.d.). With fewer cardiomyocytes, the heart is unable to contract sustainably, leading to heart failure (Orogo et al., 2013). 


Time is a crucial factor in one’s survival chances after experiencing a MI. Since the process of necrosis happens rapidly, it is critical to respond quickly, as receiving treatment faster can lessen the amount of damage done to cardiac tissue, ultimately increasing one’s survival rate.


Alarmingly, researchers estimate that 22% to 60% of all heart attacks are silent MIs, representing the cases where the patient was either asymptomatic, experienced mild symptoms, or did not connect the symptoms to a MI, leaving many MI patients untreated (Cleveland Clinic, 2024). As a result, myocardial infarction can form severe complications, including irregular heart rhythms (arrhythmias) and heart failure due to the damage done to the heart muscle (myocardium). For this reason, intervention during a MI is critical, since the condition itself may not be directly fatal, but the ensuing events that it triggers afterwards may be life-threatening.


The Promise of Tissue Engineering 

While there is an abundance of pharmacological and surgical treatments available for MI patients, the majority of them serve as symptom management or prevention of other heart complications (Mayo Clinic Staff, 2023) rather than cardiac tissue regeneration. These current treatments are insufficient, as pharmacological methods are temporary, and surgical operations may be inadequate for patients with severe cases of MI (Kitsuka et al., 2022). The only possible form of treatment with substantial improvement is heart transplants, which are restricted due to the lack of organ donors available (Isomi et al., 2019). Moreover, cardiovascular disease has continued to be the leading cause of death in the United States for over a century(Martin et al., 2024), indicating that seeking new treatments for MI beyond symptom management could be beneficial. 


A significant challenge, however, is that cardiomyocytes have limited regenerative capabilities. In fact, according to Kitsuka et al. (2022), “the regenerative capacity of the adult heart declines rapidly after birth, with less than 1% of the heart’s MCs [cardiomyocytes] being replaced each year”. After a MI, lost myocardium is replaced by fibrotic scar tissue, which is unable to contribute to proper contractions of the heart, creating a greater strain on the blood flow (Cardiac Repair and Regeneration, n.d.). That being said, unlike traditional treatments, recognized regenerative therapies serve as potential therapeutic strategies to help rehabilitate cardiomyocytes in damaged myocardium. For decades, a wide variety of stem cells have been researched for regenerative purposes. The following sections detail some of the most extensively studied methods of regeneration, along with a cell-free contender.


Induced Pluripotent Stem Cells (iPSCs)

iPSCs are cells derived from human cells that have been reprogrammed into an embryonic-like pluripotent state (UCLA Broad Stem Cell Research Center, n.d.). Due to this unique property,  iPSCs are able to differentiate into any cell type in the body and can be used for regenerative purposes. This allows for an unlimited source of human cells needed for therapeutic purposes, ranging from testing drug therapies to replacing tissues.


Various studies have tested the ability of iPSCs and differentiated cells originally from iPSCs to repair the heart after it has undergone MI. Five out of twelve studies referenced in Lalit et al. used undifferentiated iPSCs and had mixed results. Half of the studies found improved ventricular function and no presence of teratomas in immunocompetent mice. One study even found engraftment and differentiation of iPSCs into cardiomyocytes, endothelial cells, and skeletal myoblast, which are all helpful for proper cardiac function. Even with these promising results, the other half of the studies reported tumor formation, cautioning the use of iPSCs as a method for cardiac repair before more research is conducted on this area(Lalit et al., 2014). 


All other studies referenced in Lalit et al., tested different types of differentiated iPSC. Collectively, the results from these studies displayed greater consistency in safety and therapeutic benefits than the undifferentiated iPSCs. The most promising of which was a study that transplanted iPSC-derived endothelial and vascular smooth cells, which reported the mobilization of the heart's endogenous progenitor cells for recovery, increased left ventricular (LV) function, reduced scar tissue, and formation of new blood vessels. 


Similar to the findings mentioned above, numerous preclinical tests have demonstrated favorable results, particularly in animal models post-MI. However, positive results are not the only aspect that makes the application of iPSCs promising. Since they are created from one’s own body cells, the risk of immune rejection significantly decreases. Additionally, iPSCs are flexible to fit every patient's needs for recovery as they can be reprogrammed into any cell type required to repair the myocardium (Lalit et al., 2014). The main challenge researchers face with utilizing iPSCs is their efficiency, given that genetically modifying iPSC cells is a time-consuming process and some patients have distinct genetic mutations, increasing the complexity of utilizing this process. In response to this, researchers are looking to use CRISPR technology—known for its simplicity, efficiency, and relatively low cost—to reduce the amount of time spent modifying iPSCs (Moradi et. al, 2019). 


Cardiac Progenitor Cells (CPCs)

Another promising therapeutic method for cardiac regeneration focuses on cardiac progenitor cells (CPCs), a type of stem cell with limited differentiating capacity found in the heart. Differentiation capacity refers to a stem cell's ability to transform into specialized cell types, like a nerve, muscle, or blood cell. These progenitor cells are known to play a role in cardiomyocyte repair, where they are activated only after injury (Bryl et al., 2024). Since CPCs are stem cells, they are able to develop into various specialized cells, including cardiomyocytes. 


Ongoing studies suggest that, beyond differentiating into a different cell, CPC’s main action could also be to provide local protection to injured endogenous cardiac tissue. In past preclinical trials where adult mammalian hearts of mice, rats, pigs, and humans with MI damage have been used (Bryl et al., 2024), researchers injected CPCs directly into the myocardium of the hearts, and this resulted in the reduction of myocardial scars and the preservation of left ventricular (LV) function in some cases. This finding is extremely promising, given that the left ventricle is crucial for pumping oxygenated blood to the rest of the body and thus highly vulnerable to MI due to its heavy workload.


For instance, Beltrami et al.’s study isolated Lin− c-kitPOS, a type of clonogenic, self-renewing, and multipotent CPC found in the adult heart. In this study, they injected Lin− c-kitPOS into the hearts of rats who experienced a MI and found that when these cells (or their offspring) are injected into the heart, they form a well-differentiated myocardium that encompasses up to 70% of the left ventricle, indicating significant tissue regeneration. This differentiated myocardium develops through the formation of new blood vessels and myocytes that are smaller in size, but contain the same properties as regular young myocytes. Furthermore, after a few weeks, they discovered that the injected Lin− c-kitPOS regenerated over 50% of contractile myocytes and vascular cells typically found in the myocardium (Beltrami et al., 2003). 


Despite promising results from previous clinical trials, scientists are not entirely convinced that CPCs can exceed the clinical stage. In fact, the Cardiomyocyte Regeneration Consensus Statement stated that: (1) the CPCs’ role in generating new cardiomyocytes in adults is at very low rates, and that (2) the primary method of cardiomyocyte renewal is through the growth and division of already existing cells, not from the generation of new cardiomyocytes from CPCs in 2017. To summarize, CPCs have entered clinical trials, demonstrating that it is a safe option; however, their limited beneficial effects and the lack of phase III data are restricting CPCs from going past the clinical stage (Alonaizan et al., 2022). 


Exosomes: A Cell-Free Approach

In recent years, researchers have been paying close attention to extracellular vesicles (EVs), vesicles originating from the cell membrane that play a role in cell communication (Adamiak & Sahoo, 2018). Researchers have primarily been focusing on exosomes, a small type of EVs that originates from the endosomal membrane. These vesicles can be isolated and used without requiring the use of the whole cell, making exosome therapy a cell-free agent. Exosomes are unique, as their surface molecules allow them to be recognized and targeted by certain cells for interaction. Once they are attached to a recipient cell, exosomes can change the physiological state of the recipient cell through four different methods: 


1. Prompting cell signaling by using receptor-ligand interaction

2. Internalizing–a process where the cell takes up external particles into its own cytoplasm

3. Through endocytosis and/or phagocytosis

4. Fusing with the recipient cell membrane to mix their content into the cytosol (Adamiak & Sahoo, 2018). 


As shown in Adamiak & Sahoo’s study, the exosomes derived from stem cells were beneficial for the cardiovascular repair of the animals used in the experiment, including rats, mice, and pigs. For instance, the use of murine embryonic stem-cell-derived exosomes on mice with previously-diagnosed acute MI revealed improvements in post-MI cardiac function, neovascularization (the formation of new blood vessels), increased proliferation of cardiomyocytes, and furthered cardiac-progenitor cell (CPC’s) survival, proliferation, and contribution toward the repair process of the heart. The promotion of CPC use is promising in the long run, as previous studies have demonstrated that they are capable of tissue regeneration after injury. 


Furthermore, it’s important to note that exosome therapy has many advantages that differentiate it from other therapeutic candidates. As mentioned earlier, exosomes are able to be identified by target cells, giving researchers the opportunity to directly target specific tissues and cells in the process. Exosomes are also smaller, less delicate and complicated than their parent cells, making them easier to modify, fabricate, and store. In addition, since they are not stem cells, exosome therapy doesn’t present risk for tumors, immune rejection, or other complications. Finally, the limitations that come with exosome therapy aren’t significantly restricting, and researchers are currently pursuing solutions to fix these limitations. The main challenges in exosome therapy are finding the right storage conditions that would not alter their capabilities, as well as ensuring that exosomes didn’t originate from cells that were in any way physiologically disadvantaged, as exosomes can exhibit heterogeneous qualities. 


Overall, the growing popularity of the tissue engineering field has driven the search for new post-heart attack treatments, offering a possible solution to address one of the most prevalent diseases globally. Though cardiac tissue regeneration remains experimental without being widely accessible to the public, numerous clinical studies have yielded promising results that continue to provide novel findings. Remarkably, recently emerged evidence has refuted the long-established notion that the heart cannot regenerate itself and has offered a new perspective on transformative therapies in cardiovascular medicine.


Written by Nancy Morales Guzman


References

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