Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review

Abstract

Importance: Although progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist.

Objectives: To summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them.

Evidence review: Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 25, 2016. Ten randomized clinical trials and 8 systematic reviews were included.

Findings: One of the major clinical barriers facing the routine implementation of stem cell therapy in patients with cardiovascular disease is the limited and inconsistent benefit observed thus far. Reasons for this finding are unclear but may be owing to poor cell retention and survival, as suggested by numerous preclinical studies and a small number of human studies incorporating imaging to determine cell fate. Additional studies in humans using imaging to determine cell fate are needed to understand how these factors contribute to the limited efficacy of stem cell therapy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: coadministration of immunosuppressive and prosurvival agents, delivery of cardioprotective factors packaged in exosomes rather than the cells themselves, and use of tissue-engineering strategies to provide structural support for cells. If larger grafts are achieved using these strategies, it will be imperative to carefully monitor for the potential risks of tumorigenicity, immunogenicity, and arrhythmogenicity.

Conclusions and relevance: Despite important achievements to date, stem cell therapy is not yet ready for routine clinical implementation. Significant research is still needed to address the clinical barriers outlined herein before the next wave of large clinical trials is under way.

Figure 1. A major clinical hurdle is poor stem cell survival and retention post-delivery

Most trials published to date have employed intravenous, intracoronary, or intramyocardial delivery of autologous bone marrow mononuclear cells to treat both ischemic and non-ischemic heart diseases. Although a dose of 100 million cells are delivered, typically only a small fraction of cells (<5%) are retained at the site of transplantation after 24–48 hours in humans. Of those that are retained at the site of transplantation, many (~99%) do not survive beyond 4–6 weeks, as demonstrated in preclinical studies. Poor cell retention and survival likely limit improvement in LVEF and the incidence of MACE, although these issues have not been well studied (*denotes data that are only available in humans). SCs: stem cells; LVEF: left ventricular function; MACE: major adverse cardiac events.

Figure 2. Potential solutions to clinical hurdles faced by the implementation of adult progenitor cells and pluripotent stem cells

Unlike adult stem cells, pluripotent stem cells such as ESCs and iPSCs can be differentiated into cardiomyocytes, which can generate new myocardial tissues. However, when cell death is pervasive, the extent of “neomyogenesis” and their subsequent functional output is debatable. Nevertheless, imaging technologies can be used to better identify strategies that can improve cell survive, engraftment, and efficacy. Pluripotent stem cells also face additional hurdles. ESCs require immunosuppression and face difficult regulatory and ethical challenges, whereas iPSCs may not be economically feasible (yet). Both cell types will likely require antiarrhythmic therapy if large grafts are achieved. ESCs: embryonic stem cells, iPSCs: induced pluripotent stem cells, Rx: treatment.

Figure 3. Schematic of how tissue engineering can be incorporated into stem cell therapy

Patients with heart disease can be treated with different cell sources, including autologous iPSCs, allogenic ESCs, and adult stem cells. Human iPSCs are generated by reprogramming adult somatic cells that are isolated from blood, skin or renal epithelial cells into the pluripotent state, and then differentiating them into cells that can repair the heart (e.g., cardiomyocytes, endothelial cells, smooth muscle cells, or fibroblasts). Similarly, ESCs can be differentiated into cell derivatives (e.g., cardiomyocytes, endothelial cells, smooth muscle cells, cardiac fibroblasts, etc.). By contrast, adult stem cells such as bone marrow mononuclear cells, mesenchymal stem cells, cardioprogenitor cells, and cardiosphere-derived cells do not require reprogramming or differentiation. To improve their survival post-transplantation, these cells can be genetically altered to express pro-survival genes using CRISPER/Cas9, transplanted together with trophic factors, or embedded in scaffolds or hydrogels. These cells together with their adjuvant agents can be delivered as an injectable scaffold, patch, or 3D tissue construct to further improve cellular retention and efficacy.