A Comparatively Simple Approach to Improve Engraftment of Transplanted Cells

The issue with first generation cell therapies for regenerative medicine is that transplanted cells near entirely fail to engraft into tissue. There are exceptions, but for the most part, the cells used in therapy die rather than take up productive work to enhance tissue function. Where benefits occur, they are mediated by the signals secreted by the transplanted cells in the brief period they remain alive. Mesenchymal stem cell therapies that reduce chronic inflammation for some period of time are an example of the type. They are good at that outcome of reduced inflammation, but highly unreliable when it comes to any other desired result, such as increased regeneration.

Thus an important goal in regenerative medicine and tissue engineering circles is to solve the issue of engraftment, and enable the reliable delivery of cells that survive to participate in improving tissue function. Numerous strategies have been tried, with varying degrees of success. The best to date is to provide cells with a surrounding biodegradable scaffold that incorporates supporting nutrients and signals. This can work quite well when cells are allowed to form a pseudo-normal tissue like structure prior to transplantation, for example in heart patches or retina patches. The research noted here offers quite a different and much simpler strategy to improve engraftment rates, the removal of lower quality cells from the cell population created for transplantation.

Biomedical engineers believe they can aid the failing heart by using pluripotent stem cells to grow heart muscle cells outside of the body, and then injecting those muscle cells or adding a patch made from those cells, at or near the site of the dead heart tissue. Experimental and clinical trial evidence with this approach has shown moderate improvement of the pumping ability of the heart's left ventricle. However, the ability of the delivered cells to remuscularize the heart and improve cardiac function depends on the quality of those cells. A challenge has been low rates of engraftment by the transplanted cells.

Researchers now report a simple method to improve the quality of the delivered cells, and they found that this method - tested in a mouse heart attack model - doubled the engraftment rate of the injected stem cell-derived cardiomyocytes. The robust approach to select functionally competent, intact-DNA cells from a heterogeneous population can be easily adopted in clinical settings to yield cells that are better able to repopulate the ischemic myocardium and improve the performance of a failing heart.

Cardiac cell transplantation requires millions of stem cells or their differentiated derivatives. Cell propagation under accelerated growth conditions is a common way to get these large numbers of cells; but accelerated growth causes culture stress, including lethal DNA damage. These DNA-damaged cells are not suitable for cell transplantation and have to be removed from cell preparations. The researchers found they could activate transcription factor p53 in induced pluripotent stem cells to selectively induce programmed cell death, or apoptosis, specifically in DNA-damaged cells, while sparing DNA damage-free cells. They used Nutlin-3a, an MDM2 inhibitor, to activate the p53. After Nutlin-3a treatment, the dead cells were washed from the culture, and the remaining DNA damage-free cells were cultured normally and differentiated into cardiomyocytes.

The researchers then injected 900,000 of the derived cardiomyocytes into the border zone in the left ventricle of the mouse heart attack model. Four weeks later, the researchers found a significantly higher engraftment rate, about 14 percent, in hearts that received the DNA damage-free cardiomyocytes. Engraftment of the control derived cardiomyocytes was about 7 percent. "As this is a small molecule based approach to select DNA damage-free cells, it can be applied to any type of stem cells, though selection conditions would need to be optimized and evaluated. Other stem cell approaches for diseases such as neurodegenerative diseases, brain and spinal cord injuries, and diabetes might benefit by adopting our method."

Link: https://www.uab.edu/news/research/item/10661-a-simple-method-to-improve-heart-attack-repair-using-stem-cell-derived-heart-muscle-cells

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