Among the various treatment regimens being investigated, cell therapies have achieved the furthest development in human medicine. With the paucity of donor organs and long-term immunosuppressive treatment, replacement of damaged cells within the cardiac tissue with stem or primary cells have offered hope to treat heart failure. The choice of cell type for this application is assured by its accessibility, the risks it may pose and their application in clinical practice. While many other types of cells are under investigation, pluripotent stem cells (PSCs) derived from the embryos namely embryonic stem cells (ES cells) have shown unique and extraordinary capabilities in regenerative medicine. Nonetheless, due to their highly expandable nature and ability to differentiate into various cell types including tumor cells, these cells were never tested in clinical trials until recently.
A recently published study dictates the outcome of clinical trial implementing the use of human ES cell-derived progenitors in severe heart failure. This study represents the first clinical testing of human ES cells in patient suffering from cardiac disease. The trial recruited 6 patients from 2013 to 2016 with diagnosis of severe left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 35%, which is characterized as severe class III ischemic heart failure according to New York Heart Association (NYHA). After taking all safety measures into considerations, the group was granted approval for delivering ES cells in vivo by French regulatory agency after 10 years of encouraging preclinical and translational results. The first clinical case report of this trial was initially submitted in European heart journal in 2015 which presented the details of their approach and 3 month follow up results from a single patient involved in the clinical trial.
In the presented trial, ES cells were obtained from human I6 line and expanded to desired number of cells required for transplantation in a clinical grade environment. As the heart is derived from the mesoderm, commitment of ES cells towards mesodermal lineage was induced by bone morphogenic protein BMP-2 while reduction of fibroblasts growth was maintained by its inhibitor SU-5402. The purified population of stem cells was sorted by expression of stage specific embryonic antigen (SSEA-1, marker for loss of pluripotentcy) co-expressed with cardiac transcription factor Isl-1. These cells were incorporated into fibrin patch and delivered into pocket created between pericardium and epicardium at the same time of coronary bypass.
Upon 1 year follow up, authors observed no complications related to the surgery. Patient’s cardiac functional status showed remarkable improvement with LVEF increased by 12% and reduction in LV end diastolic and end systolic volumes owing to integration of the grafted cells into the heart tissue. An internal cardioverter defibrillator neither showed any signs of ventricular arrhythmias, nor were there any tumor like formations in the heart detected by computed tomography (CT) and %uFB02uorine-18 deoxyglucose positron emission tomography (PET) scans performed at 6 months (PET scan) and 12 months (CT scan) post operatively. Also, no immunosuppression related adverse events were evident. Additional analysis confirmed that delivery of the ES cells patch not only revascularized the infarcted area but also significantly improved the wall motion of cell/patch treated segment of the heart.
By demonstrating that human ES cells can be differentiated in clinical grade cardiovascular progenitors, the authors have confirmed the scalability and pluripotentiality of these cells which can be now safely delivered in patients with heart disease. Thus, encouraging results from this study has certainly provided an insight for taking cell-based therapies from bench to bedside.
- Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Parouchev A, Cacciapuoti I, Al-Daccak R, Benhamouda N, Blons H, Agbulut O, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Charron D, Tartour E, Tachdjian G, Desnos M, Larghero J. Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction. J Am Coll Cardiol. 2018;71(4):429-438.
- Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Cacciapuoti I, Parouchev A, Benhamouda N, Tachdjian G, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Guillemain R, Suberbielle Boissel C, Tartour E, Desnos M, Larghero J. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur Heart J. 2015;36(30):2011-7.
Keerat Kaur is a postdoctoral fellow at Icahn school of Medicine at Mount Sinai in department of cardiology, NY. Her research focuses on reprogramming non-cardiacmyocytes to cardiomyocytes using modified mRNA approach.