Date: 18th September 2020
Cell transplants are a highly attractive potential therapy to regenerate damaged cardiac tissue. However, translation into the clinical has been hindered by poor rates of cell retention and engraftment. Now scientists use exosomes secreted by stem cell-derived cardiac cells to improve recovery from myocardial infarction in pigs.
Cardiovascular diseases (CVDs) are the number 1 cause of death globally, taking an estimated 17.9 million lives each year. Whilst, human induced pluripotent stem cells (hiPSCs) have been shown to be a promising source of cardiomyocytes (CMs), smooth muscle cells (SMCs), and endothelial cells (ECs) for use in regenerative myocardial therapies, their translation into clinical therapeutics has been limited. This is due to low levels of cell engraftment, and safety concerns regarding the cells’ potential roles in tumourigenesis and ventricular arrhythmia.
As the levels of cell engraftment are low, many of the cardiac benefits that have been observed have been credited to the paracrine activity of the cell. Paracrine factors are often packaged by the cell into exosomes, tiny membrane-bound sacs, which transport their cargo to other cellular targets.
Now scientists led by Jianyi Zhang, from the University of Alabama at Birmingham, US, have harnessed the power of exosomes isolated from hiPSC-derived cardiac cells and have shown that this acellular strategy can improve myocardial recovery in infarcted pigs without increasing the frequency of arrhythmogenic complications.
The team started by isolating exosomes from hiPSC that had differentiation into the 3 main cells types of the heart, CMs, SMCs and ECs. As exosomes have a well-established role in angiogenesis, which is an essential protective and regenerative property, the team started by testing the exosomes in vitro. All 3 cell types of isolated exosomes promoted EC tube formation and microvessel sprouting showing enhanced angiogenic activity. Furthermore, they also protected CMs against hypoxic damage, which occurs in several cardiovascular disorders, and this was by reducing apoptosis.
These promising results drove the team to test the exosomes in a more clinical relevant system. They therefore compared transplanting a mixture of whole cells – CMs, SMCs and ECs – with exosomes produced by these cells in a porcine model of myocardial infarction. Cardiac function was assessed 4 weeks post infarction and cell or exosome transplant. They found that both cell transplants and exosome treatments were associated with a similar improvements in cardiac function, wall stress, infarct size, and cardiac hypertrophy when delivered to the infarct region of swine hearts.
As the team further analysed the treated hearts they found that both treatments also promoted similar levels of angiogenesis, proliferation, cell survival, and the expression of promigratory molecules. Therefore, suggesting that transplanted cells induce many of these benefits via paracrine mechanisms that can be mimicked by the acellular treatment of exosomes alone.
A common concern for CM transplants is the increased incidences of cardiac arrhythmia which has been previously reported in monkeys. So would exosomes therapy alleviate this adverse effect? Well interestingly here neither of the treatments altered the electrical stability of infarcted swine hearts, and both were equally as likely to display arrhythmia when it was induced via programmed electrical stimulation. This anomaly may be due to differences in dosage of cells , regions in which transplanted cells were administered or differences in experimental species. It is likely to be an important future study.
Finally, the team showed that both treatments were able to improve the cellular energy metabolism of the treated heart, deficiencies in cellular ATP metabolism are believed to contribute to the progressive decline in myocardial function that occurs in hypertrophic and heart failure patients. Thus, both cell and exosome treatments prevented or reversed at least some of the changes in myocardial energy metabolism that occur in response to infarction.
Conclusions and future applications
The team here have demonstrated the feasibility of hiPSC-derived cardiac cell exosomes as a potential therapy for cardiovascular disease. hiPSCs are derived from patients own cells to avoid eliciting an immune response that attacks and kills the cell therapy. However, this personalised approach, is expensive and the cells may require unconventional methods of storage and transport, restricting their widespread use. Exosome therapy, which appears to replicate many of the same cardioprotective and regenerative effects of cell therapy, uses non-living cellular material and consequently may be more easily translated to the clinic.
One area the team are likely to explore is more amenable deliver systems for the exosome therapy. Here, it was administered during open-chest surgery, which eliminated re-administration and it is not a viable administration method if such an invasive surgery is not required. However, homing of the exosomes to the cardiac tissue could be manipulated by engineering membrane proteins to target cells of interest. This will be a crucial development for this therapy as repeated systemic administration is an ideal objective for many pharmaceutical therapies.
It is hoped that this work will pave the way for finding new, novel therapies for CVDs. It adds weights to the wave of next generation experimental therapies such as using base-editing to treat coronary disease or biohijacking macrophages to deliver drug for the treatment of atherosclerosis. Exosome therapy could address issues with safety and effectiveness that have prevented whole-cell heart therapies from reaching clinical adoption and could open the door to treating other diseases.
Gao, L., L. Wang, Y. Wei, P. Krishnamurthy, G. P. Walcott, P. Menasché and J. Zhang (2020). “Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine.” Science Translational Medicine 12(561): eaay1318.