How to Build a Heart via Decellularization

Decellularization is the process of taking a donor organ and stripping its cells, leaving behind the extracellular matrix and all its chemical cues. The organ can then be repopulated with a patient's cells, producing working tissue for transplant that will not be rejected. The donor organ doesn't even have to be human: decellularization greatly improves the prospects for xenotransplantation, such as obtaining hearts or kidneys from pigs. So far decellularization has only been used in human medicine for comparatively simple tissue structures, such as the trachea, but researchers are not very many years away from trials for decellularized hearts and other major organs. This article goes into detail on the challenges still to be surmounted at every step of the way:

The strategy is simple enough in principle. First remove all the cells from a dead organ - it does not even have to be from a human - then take the protein scaffold left behind and repopulate it with stem cells immunologically matched to the patient in need. VoilĂ ! The crippling shortage of transplantable organs around the world is solved. In practice, however, the process is beset with tremendous challenges. Researchers have had some success with growing and transplanting hollow, relatively simple organs such as tracheas and bladders. But growing solid organs such as kidneys or lungs means getting dozens of cell types into exactly the right positions, and simultaneously growing complete networks of blood vessels to keep them alive. The new organs must be sterile, able to grow if the patient is young, and at least nominally able to repair themselves. Most importantly, they have to work - ideally, for a lifetime.

The leading techniques for would-be heart builders generally involve reusing what biology has already created. Suspended by plastic tubes in a drum-shaped chamber made of glass and plastic is a fresh human heart. Nearby is a pump that is quietly pushing detergent through a tube running into the heart's aorta. The flow forces the aortic valve closed and sends the detergent through the network of blood vessels that fed the muscle until its owner died a few days before. Over the course of about a week [this] flow of detergent will strip away lipids, DNA, soluble proteins, sugars and almost all the other cellular material from the heart, leaving only a pale mesh of collagen, laminins and other structural proteins: the 'extracellular matrix' that once held the organ together.

Through trial and error, scaling up the concentration, timing and pressure of the detergents, researchers have refined the decellularization process on hundreds of hearts and other organs. It is probably the best-developed stage of the organ-generating enterprise, but it is only the first step. Next, the scaffold needs to be repopulated with human cells. 'Recellularization' introduces another slew of challenges. "One, what cells do we use? Two, how many cells do we use? And three, should they be mature cells, embryonic stem cells, iPS [induced pluripotent stem] cells? What is the optimum cell source?" Using mature cells is tricky to say the least. "You can't get adult cardiocytes to proliferate. If you could, we wouldn't be having this conversation at all" - because damaged hearts could repair themselves and there would be no need for transplants.



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