Patching Up Broken Hearts: Cardiac Cell Therapy Gets a Bioengineered Boost

Abstract

Preclinical and clinical studies for cardiac cell therapy have only seen moderate success due to poor engraftment and survival of transplanted cells. In this issue of Cell Stem Cell, Ye et al. (2014) employ a growth-factor-loaded fibrin patch and show improved cardiovascular cell survival after cell transplantation into a porcine model of ischemia reperfusion.

In recent years stem-cell-based cardiac therapy has centered on the premise that functional myocardium may be restored by transplanting cardiovascular cells derived from exogenous stem cells into injured hearts. However, poor engraftment and survival of the transplanted cells, despite the reported beneficial effects, has led to the conclusion that cell transplantation may activate endogenous repair mechanisms through stem-cell-mediated paracrine effects rather than contribute directly to cell replacement (Garbern and Lee, 2013). While interest in transplanting autologous cells such as bone marrow or mesenchymal stem cells for cardiac repair has waned due to their lack of consistent efficacy, the potential for transplantation of pluripotent stem cell (PSC)-derived cardiac cells to be more efficacious at replacing damaged myocardium remains to be demonstrated.

In a proof-of-principle study to address the effect of transplanting PSC-derived cardiac cells, Xiong et al. have previously shown that fibrin-patch-mediated delivery of human embryonic stem cell (hESC)-derived endothelial cells (ECs) and smooth muscle cells (SMCs) into mouse and swine models of ischemic myocardial injury significantly restored cardiac function and structure (Xiong et al., 2011). hESC-derived ECs and SMCs recruited endogenous stem cells into the ischemic injury area, resulting in reduced native cardiomyocyte (CM) apoptosis both in vitro and in vivo. Given the generally low retention of transplanted cells in this study, the salubrious effects were attributed at least partly to the paracrine effects of cytokines released by the transplanted cells.

In this issue of Cell Stem Cell, Ye et al. have now demonstrated that a cytokine-loaded patch and transplanted human induced PSC (hiPSC)-derived trilineage cells (CMs, ECs, and SMCs) provide synergistic effects on cardiac function in a porcine model of ischemia reperfusion (Ye et al., 2014). Consistent with the results from their prior study, the engraftment of these trilineage cells was aided by the introduction of an epicardial fibrin-based patch. However, they implemented one key additional feature—insulin-like growth factor 1 (IGF-1) microspheres—in these cell-free patches prior to transplantation. Remarkably, the presence of IGF-1 in the patch led to a sub-sequent increase in CM and vascular cell engraftment. In aggregate, the combined effects from the presence of the patch, the slow release of IGF-1, and the improved engraftment of hiPSC-derived ECs, SMCs, and CMs led to significant improvement in overall cardiac function.

These findings by Ye et al. (2014) are particularly noteworthy given that numerous ongoing preclinical and clinical studies using various cell types and delivery strategies have only seen moderate success due to poor engraftment and survival of the transplanted cells, which in turn yielded insufficient gain in cardiac function. To address these challenges, diverse biomaterial and tissue engineering technologies have emerged over the last decade, demonstrating great potential to augment the efficiency of cardiac cell therapy (Christman and Lee, 2006; Ye et al., 2013). Biomaterials can be implanted as cardiac patches or injected as hydrogels and applied as an acellular scaffold or as a delivery vehicle for cells and/or other therapeutic macromolecules. Cardiac patches can be fabricated from naturally derived biomaterials such as collagen, Matrigel, fibrin, alginate, decellularized (heart) tissues, and synthetic polymers such as polyglycolic acid and polytetrafluoroethylene (Christman and Lee, 2006; Serpooshan et al., 2013). The putative mechanisms of benefit from the epicardial patch include (1) mechanical support for the damaged tissue and prevention of adverse remodeling; (2) creation of a biomimetic microenvironment for cell migration, proliferation, and neovascularization; (3) an enhancement of the retention of transplanted cells by prevention of cell ejection after release; and (4) delivery of cardioprotective compounds by sustained release into the injured area.

To explore the potential benefit that a cardiac patch might provide to enhance transplanted cell retention and survival, Zhang and coworkers have previously explored the introduction of autologous porcine MSCs, seeded within fibrin matrices, into swine hearts after experimental myocardial infarction (MI) (Liu et al., 2004). Moreover, with the availability of PSC-derived cardiovascular cells, they examined the engraftment of hESC- and hiPSC-derived vascular cells in both mouse and swine hearts (Xiong et al., 2011, 2012). In all cases, the fibrin patch enhanced cell delivery and yielded significantly greater rates of cell engraftment, resulting in greater gain in cardiac function. In their current work, Ye et al. have grafted a cell-free but IGF-1 microsphere-loaded fibrin patch onto the epicardial surface of a swine heart after MI. The role of this patch was primarily to prevent leakage of the transplanted cells (hiPSC-CMs, ECs, and SMCs) through the injection track and provide a source for IGF-1 cell survival signal, as based on prior studies. The result from the IGF-1 loaded patch was quite remarkable: significantly greater retention and survival of trilineage cells were achieved (8.97% ± 1.8% in Cells+Patch and 4.2% ± 1.1% in Cells Only group at 4 weeks after injection as opposed to a maximum of ~2.6% reported in other studies) (Figure 1). The current work by Ye et al. (2014) significantly extended their prior work by showing that the presence of trilineage cells provides a beneficial effect that goes beyond those achieved by CM transplantation alone.

Figure 1. Comparison of Cardiovascular Cell Survival with and without a Tissue-Engineered Patch.

Schematic diagram of the experiments conducted by Ye et al. (2014) and the reported outcomes from the injection of trilineage cardiac cells derived from hiPSCs with and without an IGF-1-loaded epicardial fibrin patch.

As with all groundbreaking studies that change our basic assumptions, the current study raises a number of thought-provoking questions. For example, is it the IGF-1 release or the paracrine factors released by the transplanted cells (or both) that is improving existing endogenous CM survival in vivo? Also, given the reported arrhythmia in a prior study involving hESC-derived CM transplantation into primate hearts (Chong et al., 2014), does the absence of arrhythmia reported here indicate a greater or lesser degree of cell engraftment or an antiar-rhythmic effect from the presence of cardiac patch or IGF-1 release? Furthermore, the relatively short duration of follow-up in this study (4 weeks) precludes an assessment of the long-term function of these animals after cell transplantation. It would be important to know whether the increased CM and vascular cell engraftment can lead to improvement in cardiac function that goes beyond the duration seen with their paracrine effects. Additional studies involving the introduction of a fibrin patch with IGF-1 with and without conditioned media obtained from the trilineage cells but without cell injection may shed light on this question.

In summary, this study by Ye et al. (2014) address a critical gap in our knowledge regarding the role of tissue-engineered patches and their associated factors in promoting the survival of transplanted cardiovascular cells in a large animal model of myocardial injury. The study highlights the potential mechanisms by which the cardiac patch and the engrafted cardiac cells may contribute to myocardial repair including (1) enhanced cell retention/survival due to the cytoprotective effect of the patch and/or the released IGF-1, (2) improvement of left ventricle wall stress due to patch integration and epicardial thickening, (3) enhanced neo-vascularization in the transplant microenvironment via paracrine effects on native tissue, and (4) improvement in systolic contractile function through recovery of host myocardial protein expression. The progress made here in human cell survival after transplantation in a preclinical large animal model of myocardial injury now takes us one step closer to the use of PSC-derived cardiovascular cells in regenerative therapy.