Fight Aging!

Cell therapies involving transplantation from immune-matched donors go a long way back; think of the bone marrow transplants used in a variety of circumstances, for example. These were a way to ferry across stem cells before it was possible to extract and manage those stem cells in a clinical setting, and the approach is sufficiently advantageous and practiced to remain in use, even as cell based regenerative medicine is reaching the clinic. In the research I'll point out today, scientists take a little of that older world of patient matching to avoid immune rejection and a little of the new world of using small, easily obtained cell samples from a donor, such as blood or skin, to reprogram and culture a large number of cells of the desired type for transplantation. In this case they turn this mixed approach to heart regeneration, and demonstrate the ability to produce benefits following heart attack in monkeys.

The heart is not a very regenerative organ in mammals. Mammalian tissues span a range of willingness to heal, from the liver at one extreme, capable of regrowing lost sections, to the brain and the heart at the other, both of which exhibit little ability to recover from injury. Both ends of the range make for interesting targets for regenerative research: the liver because it seems like an easier starting point, and the brain and the heart because any improvement is significant given the present situation. Cell therapies for the heart have been underway within and outside the formal regulated system of trials for more than fifteen years, but at this point the effectiveness of the various strategies that have arisen is still something of a question mark. Better than nothing, but how much better? A wider range of approaches is available via medical tourism than has been rigorously tested, and the rigorous tests in trials and animal models have exhibited a sizable variation in outcomes. It seems clear that the methodology used is a very important determination of the outcome given the present state of the field: you can't just throw stem cells into a patient and hope for the best. That said, that strategy actually does seem to work fairly well when well-established and well-characterized cell types are used and the goal is reduction of chronic inflammation, which is why there is a high expectation of benefits to result from mesenchymal stem cell therapies for age-related joint pain and similar issues. Regenerative therapies for organs like the heart are a whole other ball game, however, and still a work in progress.

Stem cells regenerate damaged monkey heart

Cardiac muscle cells grown from the stem cells of one macaque monkey can be used to regenerate the hearts of other macaques. The transplanted cells improved the heart's ability to contract after an induced heart attack and integrated with no sign of rejection by the recipient's immune system. However, the recipient's heart did suffer from an irregular heart beat in the first four weeks after the transplant, but this passed and was non-lethal. Researchers used cardiac muscle cells derived from induced pluripotent stem cells (iPSC-CMs) from a donor instead of the patient's own cells. Donor cells are considerably easier to manufacture but increase the risk of being rejected by the recipient's immune systems. The scientists overcame this by matching a surface protein on the donor and recipient's cells that is used by the immune system to recognize foreign cells.

"We found that monkey iPSC-CMs or cardiac muscle cells derived from induced pluripotent stem cells survived in the damaged monkey heart and electrically coupled with the host heart. In addition, the heart's ability to contract was partially recovered by the transplantation. We had a hard time handling monkey iPS cells. Unlike human iPS cells, they are somewhat tricky. The condition of iPS cells are critical for generating high purity cardiac muscle cells. Also, it took a long time to get grafted cardiac muscle cells to survive in the recipients. In addition to daily treatments of immunosuppressant drugs, we made sure the surface protein major histocompatibility complex (MHC), which is used by the immune system to recognize foreign cells, was carefully matched on the donor and recipient's cells. Human embryonic stem cell-derived cardiac muscle cells have already been used in clinic as a new therapy for post myocardial infarction (MI) heart failure. But I think it will take at least a couple of years for this treatment to become more widely-used."

Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts

Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs.

The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.