Scientists have discovered a process that could transform human organ transplants

Advancing technology one rat a time.
Advancing technology one rat a time.
Image: Flickr/Jason Snyder under CC-BY 2.0
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Hundreds of people die every day while waiting for an organ transplant. A solution to this horrible reality is to make human organs readily available—by growing them on-demand in labs or even other animals.

Scientists in Japan and the US have taken a huge step in that direction. In a study published in Nature, they report to have cured mice of diabetes by transplanting mouse cells grown in rats.

To achieve this feat, researchers injected mouse pluripotent stem cells into a rat embryo. As the name suggests, these pluripotent stem cells are able to transform themselves into all types of cells. The mouse cells intermingled with rat cells, and created a chimera whose organs and tissues were almost all created from a mix of mouse and rat cells.

Crucially, however, they had modified the rat to not produce pancreatic cells. They achieved this by knocking out a gene called Pdx1. The upshot was that the pancreas in the chimera was almost completely made of mouse cells.

From left to right; rat-mouse chimera, wild type Wistar rat, wild type C57BL6 mouse. The rat-mouse chimera was generated by injecting mouse iPS cells into a rat embryo.
From left to right; rat-mouse chimera, wild type Wistar rat, wild type C57BL6 mouse. The rat-mouse chimera was generated by injecting mouse iPS cells into a rat embryo.
Image: Tomoyuki Yamaguchi

When the rat-mouse chimeras became adults, the researchers removed the animals’ pancreases and from them, isolated endocrine islets, which contain β-cells that produce insulin. The β-cells were then transplanted to diabetic mice that had lost all their native β-cells.

Every human-to-human organ transplant requires the use of drugs that suppress the immune system. Though these drugs have severe side effects, without them, the body would consider the transplanted object foreign and unleash the immune system on it. Often a transplant patient has to take these drugs for life.

Anticipating a similar reaction, the mice that received the transplant were put on mild immunosuppressant drugs. However, the scientists found they only needed to administer the drugs for five days after transplantation. Surprisingly, the few rat cells that came along during the transplant (mostly in the blood vessels in the islets) had been destroyed and replaced by the mouse’s own cells.

Scientists don’t know yet how this happened. Qiao Zhou of Harvard University, who was not involved in the research, thinks that one way this could have occurred is that, despite the mild immunosuppressant drugs, the mouse’s immune system recognized the few rat cells present in the transplantation, and destroyed them. At the same time, native mouse cells started building blood vessels to replace them.

The β-cells in mice that got the transplants functioned just as they would in a healthy mouse for more than a year, which was the complete observation period. These lab mice only live for two to three years, which makes a one-year observation fairly long. The research opens up the door for growing human organs inside, say, a pig, using the patient’s own stem cells and then transplanting the organ when it’s mature and ready.

There are, of course, many obstacles before we achieve that feat. For instance, the pancreas is a relatively uncomplicated organ, genetically speaking. Scientists only had to knock out one gene to ensure that rat cells didn’t participate in creating the organ and mouse cells could monopolize the construction. Creation of more complex organs like the heart or kidney are controlled by many more genes, which often have multiple purposes in the body, and thus will require a more complicated genetic modification technique—or some other workaround to ensure that the changes made won’t destroy some other part of the body.

In addition, mice and rats, though separate species, are close cousins. Transplanting from a pig to a human would be a bigger leap, and it will come with its own challenges. (Pigs have some organs that are roughly the same size as humans, which is why they are good candidates for future organ transplant techniques).

And maybe we won’t even have to do all that. Researchers are also trying a different tack: xenotransplantations, where organs from a different species are used without the need to create a chimera. In 2013, researchers at Northwestern University showed that endocrine islets from rats could survive and thrive in mice without the use of immunosuppressant drugs.