Heart muscle patches are thin engineered sections of tissue, lacking blood vessels because construction of microvasculature is still an unsolved challenge, and small because without blood vessels there is a size limit on engineered tissue. The study here suggests that we should be thinking of a present-day heart muscle patch, and most of its structure and cells, as a disposable vehicle to deliver only a fraction of its cells, keeping them alive long enough to engraft alongside native cells. The rest of the cells in the patch last only long enough to temporarily change the balance of signaling in an aged or injured heart. That signaling ensures that native cells alter their behavior, and it may be those cells, rather than the surviving new arrivals, that perform most of the work needed to produce some form of regeneration or lasting benefit.
It is the case that most types of modern stem cell therapy work via the beneficial signals produced by the transplanted cells in the short time before they die. Comparatively few classes of cell therapy deliver cells that stick around to some degree, engrafting and prospering in the patient, and these are largely the older, more established transplant therapies. Obviously there is a continuum between all of the transplanted cells dying rapidly and most cells engrafting to become productive members of the local population, and the research community is working its way along that line, tissue by tissue. The technology demonstration here is an improvement over past work on heart tissue, but at 10% engraftment there is clearly a way to go yet when it comes to building better approaches. Cells are fragile.
In the near future, the development of regenerative medicine for each tissue type is likely to split into two quite different approaches, a first that gives up on cells and just delivers the signals, assuming progress in the mapping and categorization of those signals, and a second that works towards more reliably replacing worn and malfunctioning native cells with new cells that survive the transfer process in large numbers. The former will most likely happen first, given that numerous research groups have been working on it for some years now, but the latter is far more relevant to human rejuvenation. The research community will need to be able to reliably replace cells of many types in order to achieve the SENS vision of repair of cell loss and atrophy. Simply adjusting the signaling to try to override the age-related reaction to cell and tissue damage is limited in the benefits it can achieve, even while those benefits can look impressive in comparison to past medical capabilities.
Large, human cardiac-muscle patches created in the lab have been tested, for the first time, on large animals in a heart attack model. Each patch is 1.57 by 0.79 inches in size and nearly as thick as a dime. Researchers found that transplanting two of these patches onto the infarcted area of a pig heart significantly improved function of the heart's left ventricle, the major pumping chamber. The patches also significantly reduced infarct size, which is the area of dead muscle; heart-muscle wall stress and heart-muscle enlargement; as well as significantly reducing apoptosis, or programmed cell death, in the scar border area around the dead heart muscle. Furthermore, the patches did not induce arrhythmia in the hearts, a serious complication observed in some past biomedical engineering approaches to treat heart attacks.
Each patch is a mixture of three cell types - 4 million cardiomyocytes, or heart-muscle cells; 2 million endothelial cells, which are well-known to help cardiomyocytes survive and function in a micro-environment; and 2 million smooth muscle cells, which line blood vessels. The three cell types were differentiated from cardiac-lineage, human induced pluripotent stem cells, or hiPSCs, rather than using hiPSCs created from skin cells or other cell types. Each patch was grown in a three-dimensional fibrin matrix that was rocked back and forth for a week. The cells begin to beat synchronously after one day.
Past attempts to use hiPSCs to treat animal models of heart attacks - using an injection of cells or cells grown as a very thin film - have shown very low rates of survival, or engraftment, by the hiPSCs. The present study had a relatively high rate of engraftment, 10.9 percent, four weeks after transplantation, and the transplantation led to improved heart recovery. Part of the beneficial effects of the patches may occur through the release of tiny blebs called exosomes from cells in the patches. These exosomes, which carry proteins and RNA from one cell to another, are a common cell-to-cell signaling method that is incompletely understood. In tissue culture experiments, the researchers found that exosomes released from the large heart-muscle patches appeared to protect the survival of heart-muscle cells.
Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm). The hCMP matures in vitro during 7 days of dynamic culture. The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force-generation suggesting a maturation process during the dynamic culture.
In vivo assessments were conducted in a porcine model of myocardial infarction (MI). The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with signiﬁcant improvements in left ventricular (LV) function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the peri-scar border zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival. The hCMP treatment is not associated with significant changes in arrhythmogenicity.