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

Abstract

Importance While progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical translation still exist that have thwarted the delivery of cell therapy to the bedside. Objective The purpose of this review is to summarize the major current hurdles for the clinical implementation of stem cell therapy and 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 June 15, 2016. Ten randomized clinical trials and eight systematic reviews were included in this review. Findings One of the major clinical hurdles facing the routine implementation of stem cell therapy is the limited and inconsistent benefit observed thus far. Reasons for this are unclear but may be due to poor cell retention and survival, as suggested by numerous preclinical studies and a handful of human studies incorporating cell fate imaging. Additional cell fate imaging studies in humans are needed to determine how these factors contribute to limited efficacy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: 1) co-administering of immunosuppressive and pro-survival agents, 2) delivering cardioprotective factors packaged in exosomes rather than the cells themselves, and 3) using tissue engineering strategies to provide structural support for cells. If larger grafts are achieved using the aforementioned strategies, it will be imperative to carefully monitor 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 hurdles outlined herein before the next wave of large clinical trials is underway.

Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix

“…Unfortunately, the clinical translation of stem cells has been limited by acute donor-cell death 1,2 . Biomaterials offer a potential niche for the maintenance and precise control of stem cell fate 3–8 .…”

Optical fluorescence imaging with shortwave infrared light emitter nanomaterials for in vivo cell tracking in regenerative medicine

“…Furthermore, it also must show a high degree of specificity and sensitivity to obtain information about the adaptively transferred cells without inducing any harmful effects to the body. To address these requirements, it is essential to develop a multifaceted imaging technique that can reach to rapid clinical adoption …”

Multiscale technologies for treatment of ischemic cardiomyopathy

“…Multiple cell types including bone-marrow-derived mononuclear stem cells, mesenchymal stem cells (MSCs), endothelial progenitors, induced pluripotent stem cells (iPSCs) and iPSC-derived CMs have been employed to remuscularize the injured heart 43 . However, clinical translation of such approaches suffers from four major limitations: (1) poor engraftment and electromechanical coupling of the therapeutic cells in heart tissue 39 ; (2) lack of robust, accurate and safe in vivo monitoring of the therapeutic cells 44 ; (3) potential arrhythmic complications 45 ; and (4) lack of methodologies to produce large numbers of patient-specific mature and functional CMs for replacing cells lost through infarction.…”