Cardiac Cell Therapy with Pluripotent Stem Cell-Derived Cardiomyocytes: What Has Been Done and What Remains to Do?

Abstract

Purpose of Review Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide clinical trials are imminent. However, despite notable advances, several challenges remain. Here, we review PSC-CM pre-clinical studies, identifying key translational hurdles. We further discuss cell production and characterization strategies, identifying markers that may help generate cells which overcome these barriers. Recent Findings PSC-CMs can robustly repopulate infarcted myocardium with functional, force generating cardiomyocytes. However, current differentiation protocols produce immature and heterogenous cardiomyocytes, creating related issues such as arrhythmogenicity, immunogenicity and poor engraftment. Recent efforts have enhanced our understanding of cardiovascular developmental biology. This knowledge may help implement novel differentiation or gene editing strategies that could overcome these limitations. Summary PSC-CMs are an exciting therapeutic prospect. Despite substantial recent advances, limitations of the technology remain. However, with our continued and increasing biological understanding, these issues are addressable, with several worldwide clinical trials anticipated in the coming years.

Cellular Heterogeneity of Pluripotent Stem Cell Derived Cardiomyocyte Grafts is Mechanistically Linked to Treatable Arrhythmias

“…Firstly, because the primary focus was to study EAs rather than show functional improvement, both infarct and sample sizes were small. Secondly, as in most other large animal PSC-CM pre-clinical studies 8–11 transplantation experiments were conducted in the sub- acute phase post-MI, despite planned clinical trials likely to be conducted in patients with chronic ischaemic heart failure 18, 20 . Thirdly, only a single, embryonic stem cell line was assessed, with further work using induced PSC-CMs (iPSC-CMs) produced under good manufacturing practice an active pursuit of our group.…”

“…Several clinical trials are now in planning or recruitment stages worldwide 14–18 . However, hurdles to widescale clinical translation remain 19, 20 . The most concerning of these relates to ventricular arrythmias which ensue following intramyocardial PSC-CM delivery, hereafter referred to as engraftment arrhythmias (EA) 8–12 .…”

To Repair a Broken Heart: Stem Cells in Ischemic Heart Disease

“…Nonetheless, clinical trials have been or are currently being conducted to study the effects of PSC-derived cells in IHD patients. Two studies have been set up to test direct transplantation of PSC-derived cardiomyocytes [ 102 ]; HEAL-CHF has been evaluating the effect of epicardially injected PSC-generated cardiomyocytes on heart failure patients with indications for coronary artery bypass graft (CABG) [ 89 ], while LAPiS, a phase I/II clinical trial with an estimated completion date in 2024, will similarly be assessing the effect of iPSC-derived cardiomyocyte spheroids on heart failure patients, more than one month after an episode of MI with a low ventricular ejection fracture (LVEF), through injection [ 90 ].…”

Combining Cell Technologies With Biomimetic Tissue Engineering Applications: A New Paradigm for Translational Cardiovascular Therapies

“… 15 Notably, none of the six patients showed arrhythmia, tumor formation, and nor immunoreaction. 15 Current ongoing iCM-based clinical trials, as extensively reviewed elsewhere, 19 include the BioVAT-HF (NCT04396899) in Germany and the HEAL-CHF (NCT03763136) in China, which aim to treat patients suffering from heart failure and are actively recruiting patients for either the surgical implantation of an iCM-based cardiac patch or the direct injection of iCMs to the epicardium, respectively ( Table 1 ). The results of these trials are eagerly awaited.…”