Image credit: Image made by Sven Bulterijs using images from: monkey (André Ueberbach), fibroblast cells (IvanLanin), iPS stem cells (Commonwealth Scientific and Industrial Research Organisation, CSIRO), heart muscle (OpenStax College, Regents of University of Michigan Medical School), and heart attack (Blausen Medical Communications, Inc.).
In 2006 the group of Shinya Yamanaka developed a protocol to turn ordinary skin cells into stem cells. Stem cells generated in this way are called induced pluripotent stem cells or iPS cells for short. Yamanaka was awarded the 2012 Nobel prize in Physiology and Medicine for this revolutionary discovery.
Now another group of Japanese scientists have used his model to turn skin cells from monkeys into iPS cells followed by conversion into heart cells and use of these heart cells to repair the hearts of the monkeys from the damage caused by a heart attack. The results were published last Monday in Nature. Also read this Longevity Reporter article
about this new study.
The problem with autologous transplants
Patients, or in this case experimental animals, can either be treated with stem cells extracted or produced via the iPS method from their own cells (autologous) or from cells from another donor (allogeneic). While using cells from the patient itself offers the great benefit of completely preventing the risk for immune rejection, it will likely be unfeasible to bring such therapies to the market. The two main roadblocks are firstly the fact that producing individualized cell therapy is a laborious and expensive process. For example, for autologous stem cell treatment cost estimates have run between $100,000 to over $500,000 per patient (ipscell.com
This cost is because rather than producing big batches of cells to use in many patients, these autologous treatments involve producing these cells on a laboratory scale separately for each patient. Secondly, because the cells used in the therapy would be different between individuals they could not be standardized and hence regulatory approval will be difficult. Therefore, the development of standardized allogeneic cell therapy holds a big potential.
Overcoming immune rejection
To prevent the immune rejection problem of allogenic stem cells, the monkeys were treated with methylprednisolone and tacrolimus, two standard drugs used to prevent immune rejection in human organ transplants. No rejection was observed. In a previous study from a Japanese team heart cells obtained from iPS cells were implanted under the skin of monkeys to study the immune tolerance. Four groups were studied. In the first group the immune characteristics of the donor and recipient were matched and the monkeys received an anti-rejection medicine cocktail (tacrolimus, prednisolone, and mycophenolate mofetil). In the second group the immune characteristics were mismatched and the animals received the anti-rejection cocktail. In the third group the immune characteristics were matched but the animals received only a single anti-rejection drug (tacrolimus) and finally in the last group the immune characteristics were matched but the animals received no anti-rejection drugs.
Some indications of immune response against the transplant were observed in all the groups except the first one in which the donor and recipient were matched and the full set of anti-rejection drugs was given. Animals in the first group had the highest number of transplanted heart cells that succeeded in becoming part of the tissue, followed by group 2. In group 3 and 4 little of the injected cells successfully became part of the tissue. Based on these two studies we see the need for matching the immune characteristics of the donor and recipient and the use of more than one anti-rejection drug.
Image credit: Image made by Sven Bulterijs. Monkey image from Einar Fredriksen. Based on data from Kawamura T et al. (2016)
The iPS cells were in the lab differentiated into heart cells before these heart cells were injected into the damaged hearts. The researchers showed that the new heart cells remained alive for the period of the study (12 weeks) and actually the new cells became electrically linked to the rest of the heart. At 4 weeks and at 12 weeks after transplantation the contractile function of the heart was studied and found to be improved. Importantly, the cells behaved normally and no tumor formation was observed.
A communication error
The electrical activity of the hearts was studied by ECG (the heart monitor that you see attached to sick people in hospitals) and in the first weeks after transplantation episodes of too rapid heartbeat were observed. This problem peaked 14 days after transplantation and disappeared in the weeks thereafter. Such periods of too rapid heartbeat and other electric abnormalities have already been observed in a previous study in which damaged hearts of monkeys were repaired with heart cells made from human embryonic stem cells. No such abnormalities were observed in studies with rodents showing the importance of testing such experimental treatments in monkeys before human tests. While the cause of this abnormal heart rhythm after transplantation is not known it seems to disappear over time suggesting that lack of appropriate communication between the transplant and the old cells may be to blame. As the transplant matures the communication improves and the abnormalities disappear. The reason why this problem occurs in monkeys and not in small rodents may be related to differences in the size of the heart and the heart rate (in which monkeys are more similar to humans).
The September issue of the FASEB Journal also reported a study in which animals (in this case mice) were injected with stem cells to treat a heart attack. Like in the Nature study these authors also used allogeneic stem cells but they genetically manipulated these cells to make them less immunogenic. Indeed, results from this experiment showed that mice treated with the genetically modified cells had less rejection problems.
We can imagine a future in which the hearts of people who suffered from a heart attack are repaired by injecting human heart cells produced in a factory. This factory would produce cells that have been genetically engineered to be immuno-tolerant.
Chong JJ et al. (2014). Human embryonic-stem-cell-derived cardiomyocytes regenerates non-human primate hearts. Nature 510: 273-277.
Huang X-P et al. (2016). Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart. FASEB J 30(9): 3069-3082.
Kawamura T et al. (2016). Cardiomyocytes derived from MHC-homozygous induced pluripotent stem cells exhibit reduced allogeneic immunogenicity in MHC-matched non-human primates. Stem Cell Reports 6: 312-320.
Shiba Y et al. (2016). Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature [Epub ahead of print].