Growing a new heart in culture on an old scaffold

Scientists at the University of Minnesota have created new beating hearts in culture using a technique called decellularization:

Decellularization is the process of removing all of the cells from an organ -- in this case an animal cadaver heart -- leaving only the extracellular matrix, the framework between the cells, intact.

After successfully removing all of the cells from both rat and pig hearts, researchers injected them with a mixture of progenitor cells that came from neonatal or newborn rat hearts and placed the structure in a sterile setting in the lab to grow.

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Researchers hope that the decellularization process could be used to make new donor organs. Because a new heart could be filled with the recipient's cells, researchers hypothesize it's much less likely to be rejected by the body. And once placed in the recipient, in theory the heart would be nourished, regulated, and regenerated similar to the heart that it replaced.

Basically, as I understand it, you take a whole rat heart and use a solution of enzymes to remove all the cell leaving the scaffold for that organ -- called the Extracellular Matrix (ECM) intact. Then you seed heart progenitor cells into the matrix in culture. These cells will adhere and differentiate into a new heart. These scientists show experimentally that the new heart will start beating in about 8 days.

I think this is a brilliant idea, but I have some unanswered questions. (I haven't read the paper yet.)

First, the idea here is that you would limit rejection of the new organ by removing the cellular constituents. A large part of immune rejection of transplant organs occurs because proteins from the transplanted cells are presented on their surfaces by carrier proteins called MHC molecules. The host organism recognizes the MHC molecules and the presented proteins as foreign and triggers an immune response against them. Therefore, by removing the cellular constituents of the heart and replacing them with the hosts own cells it should be -- in theory -- possible to remove this aspect of rejection.

My question is whether the other means of rejection are applicable. For example, cells called macrophages devour acellular foreign material which is also presented to activate the immune system. Wouldn't the foreign scaffold be subject to the same inspection?

There are two good reasons to suggest that it would not. The first is that the proteins that make up the ECM -- mostly collagen -- are big and stable. It is certainly possible that these proteins are so big and so stable that they simply would not be degraded and presented to the immune system. The second is that ECM proteins are probably highly conserved within members of a species and between related species. It is certainly possible the proteins between the donor and the recipient would be so similar that they would not be recognized as foreign. (A similar principle is employed when we use blood-type matching to pair donors and recipients for transplanting.)

I don't know if I think a heart made in this way would require no rejection drugs, but it sounds like it would require substantially less drugs.

Second, I wonder about whether the new organ actually works. They say that it starts pumping, but does it really function. Their idea is predicated on the premise that the cells differentiate on the new scaffold into a relatively functional state. They mention in the abstract that the cardiac function of the new heart is reduced: "equivalent to about 2% of adult or 25% of 16-week fetal heart function." Thus, whether a fully functional organ can be created is still speculation.

That being said, if this works out the applications are essentially limitless. All solid organs have an ECM scaffold of some kind. If this technology could be paired with embryonic or adult stem cells, we could create a nearly limitless supply of replacement human organs using the scaffolds of some related species like pigs. For that reason, this is some brilliant work.

The paper is here. I'll read it later and see if I have anything to add.