Stripping donor hearts and repopulating them with recipient-derived stem cells

A partially recellularized human whole-heart cardiac scaffold, reseeded with human cardiomyocytes derived from induced pluripotent stem cells, being cultured in a bioreactor(Credit: Bernhard Jank, MD, Ott Lab, Center for Regenerative Medicine, Massachusetts General Hospital)

Heart transplants have been around since 1967, but they're still anything but routine. In an effort to ensure a steady supply of compatible organs, a team of scientists from Massachusetts General Hospital (MGH) is working on ways to create bioengineered human hearts by first stripping donor hearts of cells that could provoke an immune response in a potential recipient, and then using the recipient's own induced pluripotent stem cells (iPSCs) to generate cardiac muscle cells that can be used to repopulate the heart in an automated bioreactor system.

Every year, 800,000 people worldwide have heart conditions that require a transplant. Unfortunately, there are only enough suitable donor hearts for around 3,500 operations. Part of the reason for this isn't that there aren't enough healthy hearts donated to go around, but that a heart needs to be biologically compatible with the recipient.

And even if there is an extremely close tissue match, the recipient's body will treat still the new heart as alien and attack it. To prevent this tissue rejection, the recipient's autoimmune system must be suppressed by a battery of pills for a lifetime, combined with another battery of pills to correct the damage caused by suppressing the immune system.

What the MGH team led by Dr Harald Ott is trying to achieve is a way of turning the alien heart into a not-alien one. In other words, to make it as much like the recipient's original heart from a cellular point of view. This way, the body is less likely to reject it and the follow-up medical regime can be less aggressive.

The MGH approach to essentially take a donor heart, strip it down and rebuild it – much as one might strip a house down to its frame and then rebuild it with all-new materials. The heart, like most organs, consists of living cells that are held in place by a connective matrix made of collagen fibers. It's the living cells that allow the heart to pump blood, but they're also what spark an immune reaction in the host body, so the idea is to remove the original cells, then replace them in the remaining collagen matrix with cells created from the recipient's own. Since the new cells are genetically identical to those of the recipient, tissue rejection is less likely.

According to MGH, Dr Ott had already developed a procedure in 2008 that allowed him to remove living cells from organs using a detergent solution. The MGH team then used the leftover extracellular matrix as a scaffold that can then be repopulated with new cells. In this way, they could not only create working rat lungs and kidneys, but also decellularized large-animal hearts, lungs, and kidneys.

The next step was to scale up the method on a whole human heart. This was done by creating iPSCs. The iPSCs are made by using a new method to reprogram skin cells with messenger RNA factors so they revert to an embryonic state.

These all-purpose stem cells can then be induced to become any kind of cell in the human body. In this case, they were turned into cardiac muscle cells, or cardiomyocytes. According to MGH, this method not only is more efficient and allows for creating cells in large enough quantities for clinical use, but it also avoids many regulatory obstacles that more conventional methods come up against.

These cardiac cells were then introduced into 73 decellularized human hearts from donors who were brain dead or had suffered cardiac death. The hearts selected weren't suitable for transplant, so were used with consent for research purposes. The cells were reseeded into the 3D matrix of the left ventricular wall of the decellularized hearts as thin slices, then as 15 mm fibers, which began to contract on their own within days.

The hearts were then placed for 14 days in an automated bioreactor system developed by the MGH team. This provided the tissues with nourishment in the form of a solution while ventricular pressure and other stressors were applied to exercise them. The researchers say the result was dense regions of iPSC-derived cells that resembled immature cardiac muscle tissue and contracted like heart tissue when subjected to electrical stimulation.

"Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial patch that could replace cardiac tissue damaged due to a heart attack or heart failure," says Jacques Guyette, PhD, of the MGH Center for Regenerative Medicine (CRM). "Among the next steps that we are pursuing are improving methods to generate even more cardiac cells – recellularizing a whole heart would take tens of billions – optimizing bioreactor-based culture techniques to improve the maturation and function of engineered cardiac tissue, and electronically integrating regenerated tissue to function within the recipient's heart."

The team's results were was published in Circulation Research.

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