This paper of the month (Menasche et al. 2018) describes the first clinical trial aiming to use human embryonic stem cell (ESC) derivatives to improve cardiac function after myocardial infarction. It is highly significant that it was done at all, and its existence as much as the results represent a step change for the field.
Six patients were treated: they each had poor cardiac function after a myocardial infarction more than 6 months previously. The team seeded fibrin scaffolds with human ESC differentiated to the cardiac progenitor stage, at which point the cells can further differentiate to cardiac muscle cells (cardiomyocytes) or those forming blood vessels (endothelial or smooth muscle cells). The patch was attached to the surface of the heart during an open-chest procedure to perform coronary bypass grafting (CABG).
The use of pluripotent stem cells, either embryonic (ESC) or induced by reprogramming from somatic cells such as skin (iPSC), has become increasingly attractive as protocols to differentiate them into highly pure population of e.g. cardiomyocytes have improved. Competing adult stem cells from bone marrow or other sources have been used much more widely in clinical trials and shown to be largely safe, but their ability to generate cardiac muscle has been disappointing.
However, there have always been significant safety concerns for pluripotent stem cells. Formation of tumours called teratomas from undifferentiated ESC/iPSC is not only possible but expected- this is one of the ways to prove you have a genuine pluripotent population. This risk disappears when the cells are driven into any differentiated phenotype, but it has to be shown that all undifferentiated cells have disappeared. In this recent study (Menasche et al. 2018) they used magnetic sorting to increase the purity of their preparation so that <0.1% undifferentiated ESC remained.
Then there is the question of immune suppression: this is certainly necessary for ESC, though patient-derived iPSC hold out the hope that cells could be matched to the individual and evade immune attack. The immunosuppressant protocol used here was light and was stopped after one month: this was justified as reducing potential harm and because their current hypothesis emphasised the early paracrine effects of ESC-derived progenitors as the beneficial mechanism. The appearance of antibodies to the grafted cells in three patients, though clinically silent, shows that the ESC-derived progenitors had produced an immune response.
In terms of safety, no tumours were seen and there was also no evidence of increased arrhythmic events (which had been observed when hESC-derived cardiomyocytes were used in large animal experiments). One patient died shortly after the operation and one 22 months after from heart failure. Neither of these deaths would be unexpected in this high-risk population and neither was directly linked to the graft. Some improvement was seen in cardiac motion in the area of the patch, but the investigators are rightly cautious in ascribing this to the graft since it could have been due to the coronary artery grafting done at the same time, and because of the relatively small number of hESC-derived progenitors used.
Though the conclusions of this study are modest, it represents an important foot in the door for pluripotent stem cells in therapy, and the amount of logistical, regulatory and ethical barriers that the investigators have surmounted should not be underestimated.
Menasche, P., et al. (2018). “Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction.” J Am Coll Cardiol 71(4): 429-438.