While giving my stem cells some much-needed attention in the lab this morning, I reflected on another great ISSCR annual meeting. I’ve gone to this meeting every year since enrolling in graduate school and each year, I thoroughly enjoy listening to talks across the breadth of stem cell research.
Over the years I’ve noticed a pattern. My favourite talks at ISSCR are always given by researchers who have ‘stepped up their game’ and really put their vision for regenerative medicine to the test. Last year, my favourite talk was given by Hiromitsu Nakauchi, in which Nakauchi described his vision of using farm animals as vehicles for human organ development (read my blog post about it here).
This year, Charles Murray topped my list. As a clinician-scientist working within the cardiac regeneration space, Murray feels that progress has been too slow. Therefore, in a field where researchers have been taking baby steps towards stem cell-mediated cardiac regeneration, Murray decided to take a leap. Murray’s group has transplanted human embryonic stem cell (hESC)-derived cardiomyocytes into non-human primates following myocardial infarction in an effort to restore heart function.
Many researchers have transplanted stem cell populations into small animal models, including Murray who has transplanted hESC-derived cardiomyocytes into guinea pig hearts. In his talk, Murray questioned whether transplanting hESC-derived cardiomyocytes into small animal models makes sense. The physiology of a mouse, rat or guinea pig is quite different from a human – how could these experiments provide insight into whether this strategy would be successful in humans? A non-human primate model would be more telling and Murray is now the first to report transplantation of hESC-derived cardiomyocytes in this system.
In the body, cardiomyocytes respond to electrical signals, which instruct these specialized muscle cells to beat, pumping blood through the circulatory system. Cardiomyocytes created in the lab from pluripotent stem cells also beat (check out this video of beating stem cell-derived cardiomyocytes). Cardiac injury such as a heart attack can leave areas of heart muscle tissue damaged, unable to efficiently pump blood through the circulatory system. In theory, transplanting new cardiomyocytes into the heart following cardiac damage should rescue any loss of contractile ability resulting from injury. However, this is no easy task. Transplanted cells must not only survive, they must also electrically integrate into the heart, meaning they must take instruction from the host’s internal pacemaker (cells within the heart that set the heartbeat pace) on when to contract (or beat).
Before Murray set out to transplant cells into monkey hearts, they first created a hESC line that would allow them to see cells as they beat under fluorescent light. The reporter cells were then differentiated into cardiomyocytes and one billion cells were injected into each monkey, two weeks following myocardial infarction. The hearts were analyzed up to three months following transplantation. Amazingly, the human cardiomyocytes electrically integrated into the host hearts and were found to be contracting under the direction of the monkey’s pacemaker. Arrhythmias (irregular heartbeats) could be detected shortly after transplantation but normal sinus rhythm (normal heartbeat pattern) appeared to be recovered over time.
In addition to electrically integrating into the heart, hESC-derived cardiomyocytes almost fully remuscularized the damaged hearts. Following myocardial infarction, hearts were left with infarct regions making up 5.3% of the left ventricle. After cell transplantation, the total engraftment area measured 4.9% of the left ventricle, or nearly the entire infarct region, a truly remarkable outcome.
While Murray’s work is very exciting, the team still has a long road ahead. More experiments will need to be performed to prove long-term efficacy (improvement in cardiac clinical measures) and safety (maintenance of normal sinus rhythm over time and lack of tumor forming ability of transplanted cell populations). If all goes well, Murray projects that it may be possible to start human clinical trials in about four years.
Shiba Y., Fernandes S., Zhu W.Z., Filice D., Muskheli V., Kim J., Palpant N.J., Gantz J., Moyes K.W. & Reinecke H. & (2012). Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts, Nature, 489 (7415) 322-325. DOI: 10.1038/nature11317
Angela C. H. McDonald
Latest posts by Angela C. H. McDonald (see all)
- Stem cells in 60 seconds: Quick lessons in communicating science - December 23, 2013
- Stem cell defects may help explain premature aging in Down Syndrome - October 16, 2013
- Taking a leap: Regeneration of the non-human primate heart - June 25, 2013