When we developed the ability to convert various cells into a stem cell, it held the promise of an entirely new type of therapy. Rather than getting the body to try to fix itself with its cells or deal with the complications of organ transplants, we could convert a few adult cells to stem cells and induce them to form any tissue in the body. We could potentially repair or replace tissues with an effectively infinite supply of a patient’s own cells.
However, the Nobel Prize for induced stem cells was handed out over a decade ago, and the therapies have been slow to follow. But a group of German researchers is now describing tests in primates of a method of repairing the heart using new muscle generated from stem cells. The results are promising, if not yet providing everything that we might hope for. But they’ve been enough to start clinical trials, and similar results are being seen in humans.
Heart problems
The heart contains a lot of specialized tissues, including those that form blood vessels or specialize in conducting electrical signals. But the key to the heart is a form of specialized muscle cell, called a cardiomyocyte. Once the heart matures, the cardiomyocytes stop dividing, meaning that you end up with a fixed population. Any damage to the heart due to injury or infection does not get repaired, meaning damage will be cumulative.
This is especially problematic in cases of blocked blood vessels, which can repeatedly starve large areas of the heart of oxygen and nutrients, killing the cardiomyocytes there. This leads to a reduction in cardiac function and can ultimately result in death.
It turns out, however, that it’s relatively easy to convert induced pluripotent stem cells (IPSC, with pluripotent meaning they can form any cell type). So researchers tried injecting these stem-cell-derived cardiomyocytes into damaged hearts in experimental animals, in the hope that they would be incorporated into the damaged tissue. But these experiments didn’t always provide clear benefits to the animals.
The group in Germany tried a somewhat different approach. Rather than disperse loose cells, they grew a sheet of cardiomyocytes, and a separate sheet of what’s called stroma—a mixed population of cells that form the connective tissue and blood vessels that help support cardiomyocytes in mature hearts. These two sheets of cells were combined into a single patch that could be attached to the heart’s exterior.
In experiments with mice, this worked to improve heart function. So the team went to a German research ethics body to check which large animal they should use for further testing before starting human trials. The answer that came back? Macaques.
Positive signs
The paper released on Wednesday describes the results from the macaque work, along with a single human heart from the ensuing clinical trial. The patient the heart belonged to later received a transplant, allowing his stem-cell-treated heart to be analyzed. And in the macaques, the researchers had a mix of animals treated with different-sized cell patches, along with controls.
Most of the work involves a basic characterization of the fates of the patches after they’re implanted, addressing many of the potential concerns associated with putting a large amount of stem-cell-derived tissues into an adult animal.
The good news is that there are a couple of significant worries that don’t seem to be issues at all. One is that immature stem cells may still be lurking among the mature cardiomyocytes, and they could go on to form tumors after implants. That wasn’t seen in this case. Another worry is that the added tissue wouldn’t be able to integrate into the hearts functionally. Cardiomyocytes in culture start contracting on their own, and people were concerned that they would continue to beat to their own rhythm rather than working in concert with the heart. But there were no signs of arrhythmias in any of the transplanted animals, suggesting the implanted sheets of cells had integrated with their surroundings.
That said, the implants were not problem-free. For one, some of them ended up with cells belonging to the cartilage/bone lineage, suggesting that there were still a few stem cells in the sheets that were not committed to a mature state.
Another problem is that one animal generated an immune response to the implanted cells despite the fact that the animals were given immunosuppressive drugs. This is a somewhat surprising problem, as it was hoped that using stem cells derived from the same animal would avoid any immune response. This is obviously something that will need to be examined further.
All that said, the grafts seemed to work. The grafts led to increased heart wall thickness and contraction, and grafted hearts moved larger amounts of blood around.
Still some questions
That said, the implants don’t seem to be the equivalent of the heart tissues they are meant to replace. While the cardiomyocytes of the implant sheets were mature, they didn’t grow to the same size as the ones in the mature heart. That may be related to another issue: The implants didn’t fully integrate into the blood supply of the heart. There are potential ways of handling this—we’ve identified a number of signaling molecules that boost the formation of blood vessels. However, testing them will require additional work in animals, which may also allow us to test whether a better blood supply improves the cardiomyocyte size.
Meanwhile, the single human heart that was available for analysis produced results that were consistent with those generated in the macaques. But we’ll have a clearer picture of whether that’s the typical result once the full data from the trial becomes available. At that point, we’ll be in a better position to evaluate whether stem cells are really ready to live up to their potential.
Nature, 20225. DOI: 10.1038/s41586-024-08463-0 Â (About DOIs).