Stem‐cell cardiospheres for myocardial regeneration: advancing cell therapy in myocardial infarction and heart failure

One out of every five men over the age of 40 are at risk of developing a heart attack at some point during their lifetime. Myocardial infarction (MI), also known as heart attack, is a clinical syndrome in which deprivation of blood flow to the heart muscle causes cardiomyocyte death and deterioration of heart function, resulting in ischaemic cardiomyopathy and eventual heart failure (HF). For this reason, HF remains the most rapidly rising heart disease globally and represents the most common cause of death in North America. The search for effective treatments of MI and HF has led to investigations into the use of stem cells including human embryonic stem cells, induced-pluripotent stem cells, cardiac progenitor cells and bone marrow-derived stem cells for heart repair and regeneration. However, current stem cell therapies have demonstrated a modest reconstitution in damaged myocardium and heterogeneous clinical outcomes. Heart regeneration is the default state in nature but its capacity is greatly diminished in human adults, creating a big challenge in developing effective cell therapy treatments. Nonetheless, cardiospheres (CSps) have recently emerged as a promising avenue for cardiac repair and regeneration in infarcted hearts. CSps are cardiac explant-derived microtissues (70–150 μm) that consist of undifferentiated stem cells in the core and an outer layer of cardiac-committed cells packaged into a specialized three-dimensional structure. This complex three-dimensional model protects the stem cells from cellular oxidative stress, resulting in their increased stemness, paracrine potency and therapeutic potential. However, implantation of CSps via conventional methods directly into damaged heart muscle raises the possibility of developing an embolism due to its three-dimensional structure. Therefore, further research is warranted to determine a suitable delivery route for CSp implantation to maximize its therapeutic potential. In a recent study by Zhang et al. (2018) in The Journal of Physiology, implantation of CSps in the pericardial cavities of Sprague–Dawley rats was performed to determine the therapeutic effects of intrapericardially implanted CSps in post-MI rats. The authors hypothesized that the regenerative potential of CSps could be further enhanced by pretreating CSps for 24 h with pericardial fluid from another subject preconditioned with MI. Notably, the authors reported that further improvement in the activity and survival of optimized CSps was achieved by encapsulating with matrix hydrogel prior to in vivo implantation. In fact, transplantation of pericardial fluid-preconditioned, matrix hydrogel-protected CSps into the pericardial activity of MI rats showed a 40% increase in cardiac function by ejection fraction, increased survival rate and significantly reduced infarct size in 1-week-, 2-week- and 4-week-old post-MI rats. The inclusion of potential mechanisms of action was a strength of the study as these data suggested that the therapeutic effects of CSps intervention in the pericardial cavity were mediated by a mechanism of paracrine effect. Taken together, these findings provide direct, compelling evidence that pericardial application of optimized CSps is an effective therapeutic strategy to treat MI in an experimental model. One unwanted outcome in any regenerative therapy is ongoing proliferation of implanted stem cells as well as ectopic proliferation. Therefore, a reliable, effective method to track and monitor the temporal and spatial migration of stem cells after transplantation is critical in determining their therapeutic potential. While the current study successfully assessed the effectiveness of CSp transplantation via in vivo tracking with the lipophilic tracker 1,1-dioctacecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) in 1-week-, 2-week- and 4-week-old post-MI rats, certain technical limitations should be considered. Berninger et al. (2017) pointed out that for most conventional agents including a carbocyanine fluorescent tracking dye, despite its high photostability and low cytotoxicity, their fluorescence signals decrease rapidly within a few days after labelling in vivo. This renders them to be better suited for initial point-of-care clinical testing rather than long-term monitoring and analysis. In the current study, Zhang et al. (2018) used this approach to monitor CSp proliferation up to 4 weeks post-MI, which may have potentially underestimated the therapeutic effects of DiR-labelled CSps. Stem cell-based therapy has acquired a promising role in regenerative medicine. However, inconsistent results and limited cardiac function improvement in a number of clinical trials indicate that many challenges in stem cell therapy remain to be resolved. One major issue in cardiac stem cell therapy is the immature differentiation of injected cells, resulting in a cardiomyocyte-like phenotype. Although Zhang et al. (2018) claimed that injected CSps can differentiate into cardiomyocytes in the current study, previous work by Sultana et al. (2015) has challenged this idea by lineage tracing studies that showed cardiac c-kit+ cells are in fact endothelial in nature and do not differentiate into cardiomyocytes. This may explain the mis-colocalization among c-kit, sca-1 and KDR expressions observed in the current study. Furthermore, poor co-staining between cTnT and DiR expressions suggests that cardiomyocyte differentiation was mediated through a paracrine effect of transplanted CSps. Nevertheless, Zhang et al. (2018) were able to demonstrate the expression of other cardiac stem cell markers including KDR and Sca-1 in CSps. Interestingly, recent studies have shown that small extracellular vesicles, also known as exosomes, are critical agents for cardiac regeneration and represent a potential therapeutic strategy in regenerative medicine. There is accumulating evidence that treatment with mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are efficient therapeutic approaches through promoting reverse left ventricular remodelling and angiogenesis in MI and HF patients (Karantalis et al. 2016). It would be of enormous interest to see if combined transplantations of optimized CSps, MSCs and EPCs could produce greater therapeutic potential and overcome existing limitations in cardiac regeneration than CSps alone. Moreover, recent studies have shown that specialized immune cells known as embryonic macrophages also play a critical role in heart repair through promotion of myocyte proliferation and blood vessel development. Without macrophages, heart regeneration is limited and the pathological progression of HF is accelerated. Interestingly, Sivanathan et al. (2017) have shown that supercharging stem cells with interleukin-17A can help them overcome cellular ageing as well as the deleterious influence of cardiac risk factors on the stemness of stem cells, resulting in enhanced regenerative potential and angiogenic cell therapy. Finally, it is important to commit to a heart-healthy lifestyle to minimize the risks of heart attack. Whether stem cell-based therapeutic approaches can substantially repair and regenerate damaged hearts in humans requires future work to improve long term tracking and therapeutic effects of implanted stem cells. Nevertheless, the significantly improved heart function following CSp transplantation in post-MI rats shown by Zhang et al. (2018) raises hope and potential for the translation of this technology. In summary, Zhang et al. (2018) have demonstrated that implantation of matrix hydrogel-packaged, pericardial fluid pre-treated CSps into the pericardial cavity significantly improved cardiac function and fibrosis following MI. These findings shed light on the modest efficacy of current stem cell-based therapies in MI and HF patients. Translationally, pericardial injection of pre-optimized CSps should be practised as a possible strategy for treatment of myocardial infarction and heart failure. None declared. All authors have reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons listed as authors qualify for authorship, and all those who qualify for authorship are listed. S.-H. L. is supported by an Ontario Graduate Scholarship and a Ted Rogers Centre for Heart Research Doctoral Fellowship. The authors apologize for not citing all relevant articles due to reference limitations.

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