Stem Cell Therapy in Cardiac Regeneration
By: Uswa Shahzad and Dr. Terrence Yau
Ischemic heart disease afflicts millions of people worldwide, and accounts for at least 50% of all cardiovascular-related deaths in the developed world1. As such, it places a significant burden on the healthcare system in terms of the cost and resources needed to manage patients with progressive to terminal cardiac dysfunction. Myocardial infarction, commonly known as a heart attack, occurs due to a partial or complete obstruction of the arteries supplying blood to the heart, and results in the death of cardiomyocytes (heart cells). A major challenge that currently exists in treating ischemic heart disease in a clinical setting is inducing repair and regeneration in the infarcted heart. In order to address this issue, tissue engineering and stem cell transplantation (Figure 1) are being extensively investigated as cardiac regenerative strategies.
Both pluripotent stem cells and adult stem cells have been explored as possible therapeutic options. Pluripotent stem cells include human embryonic stem cells and induced pluripotent stem cells, while adult stem cells include bone marrow-derived mononuclear cells such as mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and cardiac-resident stem cells, among others1. Pluripotent stem cells can differentiate into one of the three cardiac lineages consisting of cardiomyocytes, smooth muscle cells, and endothelial cells. In addition, fibroblasts can be reprogrammed to become pluripotent and subsequently differentiate into cardiomyocytes(1).
Transplanted stem cells may act in a paracrine manner by releasing factors such as vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) that promote the growth of new blood vessels(2). In addition, the transplanted stem cells may prevent further cell death of existing cardiomyocytes(3) as well as activate resident cardiac stem cells(2). While there is evidence to support both of the above mechanisms of action, a major unanswered question is whether stem cells differentiate into normal cardiomyocytes after transplantation(4), fuse with the host cardiomyocytes(5), or do both. For example, when cultured alongside cardiac cells, mesenchymal stem cells have been shown to only mimic the characteristics of cardiomyocytes(6). Most of the aforementioned adult stem cell types have been shown to improve cardiac function after transplantation into infarcted hearts, but have done so without directly differentiating into cardiomyocytes(1,2). There is some evidence to suggest that cardiac stem cells can differentiate into cardiomyocytes, although their endogenous effects are unknown(7).
The beneficial effects of stem cell therapies have not, however, resulted in normalization of infarcted heart function. In an effort to enhance cell-based therapy, genetically enhanced stem cells that have been modified to overexpress certain growth factors such as VEGF and hepatocyte growth factor (HGF). Overexpression of certain pro-survival genes like Akt-1 have also been utilized and have shown some promise(1,8).
Despite an advanced understanding of cell-based therapy in laboratory research, in the clinical setting stem cell therapy still seems to be in its nascent stage. Major clinical trials such as BOOST(9) and ASTAMI(10) have demonstrated an early improvement in heart function, but found no significant differences between groups at six months. In comparison, REPAIR-AMI(11) reported a small but significant improvement in cardiac function, as well as improvement in clinical outcomes such as recurrent myocardial infarction and repeat revascularization at 1 year.
While initial clinical trials have demonstrated the promise of stem cell transplantation for cardiac regeneration, there are still some issues that need to be addressed before this therapy can become widespread. Most studies have demonstrated that donor cell retention within the heart is optimal with direct intramyocardial injection(12). However, unsettled questions include the optimal stem cell population and dose, whether cell therapy can be efficacious in both acute and chronic ischemic injury, the optimal timing to transplant cells, and the duration of therapy. While many of these issues have been studied in animal models, translation of those findings into a considerably more complex human population is a significant challenge. There is a need for more complex animal models that take into account the comorbidities that are characteristic of the typical patient with ischemic cardiomyopathy(13).
Another issue is that the efficacy of cell transplantation is related to the number of cells that can be transplanted, engraft, and survive. Most cell therapy strategies have utilized autotransplantation in order to avoid potential problems with rejection, and the number, and perhaps, the regenerative potential of autologous donor cells is limited. Donor cells may be expanded ex vivo to obtain greater numbers, but the longer the delay in cell preparation, the more cumbersome and less practical this process becomes in clinical application. Hence, in order to address the issue of cell survival, we have utilized cell-based gene therapy as a means to augment the survival and reparative capacity of these cells, and also used transmyocardial revascularization (TMR) to treat the infarct zone prior to cell implantation.
In our previous studies, we have shown in a rat infarct model that transfection of bone marrow cells (BMCs) with proangiogenic factors, such as VEGF, prevents donor cell death and induces angiogenesis(14). Furthermore, BMCs transfected with VEGF and bFGF augmented angiogenesis and resulted in significantly increased vascular density(15). We have also shown that stem cell factor (SCF) overexpressing MSCs can mobilize endothelial progenitor cells and promote angiogenesis, resulting in increased perfusion to surviving cardiac tissue(16).
On the other hand, TMR has been used clinically in the treatment of refractory angina, and uses a laser to create channels in the ischemic myocardium. The two currently accepted mechanisms by which TMR works are denervation, which results in relief of the pain associated with angina, followed by development of new blood vessels in the ischemic tissue through angiogenesis.
We have demonstrated that pretreatment of an infarct zone by TMR enhances the effects of mesenchymal stem cell transplantation. In a rat infarct model, TMR performed prior to transplantation of MSCs or MSCs overexpressing VEGF, bFGF, and insulin-like growth factor-1 (IGF-1) resulted in significantly increased angiogenesis and restoration of ventricular function(17). In the TMR group, donor MSC survival three days after transplantation was four times greater than in the control group. Our recent work has shown that TMR induces engraftment of circulating MSC via the c-kit-SCF and CXCR4-SDF-1 signaling axes. These findings are another step towards understanding the specific mediators that play a role in survival of the transplanted stem cells and their interaction with endogenous myocardial repair mechanisms. In addition, this shows that TMR can potentially be used clinically as an adjunct to MSC transplantation to improve outcomes.
While still in development, stem cell therapy holds great promise as a treatment for ischemic heart disease. Great strides have been made in understanding how stem cells work in the infarcted heart, and clinical trials have shown that stem cell therapy is remarkably safe and may improve the function and perfusion of infarcted hearts. The magnitude of this reparative effect is still modest in complex patients with multiple comorbidities, but ongoing research to elucidate the interaction of implanted stem cells with the host myocardium and bone marrow, as well as to augment the reparative capacity of each donor cell, suggest that more efficacious stem cell therapies for cardiac repair will be devised in the near future.
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- Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 2002 Jun;73(6):1919-25.
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- Yau TM, Kim C, Ng D, Li G, Zhang Y, Weisel RD, et al. Increasing transplanted cell survival with cell-based angiogenic gene therapy. Ann Thorac Surg 2005;80:1779-1786.
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