From science fiction novelists through to medical doctors and industry leaders, a huge amount of attention has been given to the idea of growing human organs for transplantation in large farm animals like pigs and sheep. The need for organs to transplant into patients is one driving motivation (~5000 patients waiting in Canada alone), but there also exists a need for the cells that those organs would produce (e.g., insulin producing cells from pancreases to treat patients with Diabetes). Last month, a landmark study from Stanford University emerged that laid the groundwork for addressing the latter aspect: interspecies organ growth for the provision of functional cells for transplantation.
The laboratory group of Professor Hiromitsu Nakauchi, senior author of the Stanford study, originally made waves in a 2010 Cell paper when they demonstrated the ability to grow a fully rat-based pancreas in a mouse incapable of generating a pancreas. Former Signals blogger Angela McDonald wrote a great piece about this in 2012 and speculated that the study might lead to more enthusiasm for trying to grow human organs in large farm animals. What the Nakauchi group has cleverly done in this new study appearing in Nature magazine is to use the larger host animal (in this case a rat) to grow the pancreas for a smaller organism (mouse) and then use the insulin producing cells as the transplantation material into many recipients.
So, how does the whole procedure work? The first step is to have a host organism incapable of making the organ of choice (in this case a rat unable to make a pancreas due to a genetic mutation). When mouse pluripotent cells are implanted in the early rat embryo, they contribute to all tissues in the body but, importantly, because these rats cannot make a pancreas, the entire adult pancreas is “mouse cell derived.”
When the organism reaches adulthood, the pancreas is harvested from the rat and islet cells can be isolated (similar to how human cadaveric pancreases are isolated and broken apart for transplantation as islet cells, e.g., the Edmonton Protocol). These “rat grown” cells are then transplanted into mice that have been given Diabetes to test whether the cells can alleviate the symptoms of Diabetes. It turns out that the mouse cell-derived (but rat-grown) pancreatic cells performed just as well as mouse to mouse donor matched islet transplantation in stabilizing the glucose levels of mice.
One of the most important aspects of this particular study is the length of time that the researchers followed up the treated mice. The mice treated with rat-grown mouse islet cells were cured of their diabetic symptoms for more than a full year (~50% of a mouse’s normal lifespan) and there was no evidence of any rat cells in the transplantation recipients.
The researchers further showed that removal of the kidneys (where the islets were transplanted) caused the disease to return. They also provided formal evidence that the transplanted cells were comprised of all three types of hormone secreting islet cells (alpha, beta and delta) and that insulin, glucagon and somatostatin were all expressed, just as in the case of matched islet transplantations.
The reason that this study is so important is that it demonstrates for the first time that organs grown in a different (larger) species can produce the cells necessary to perform the jobs of that same organ upon transplantation.
While an enormous amount of work exists to scale this up to even consider growing human organs in large farm animals, the proof-of-principle work in rodents should definitely inspire conversations about whether we should pursue such approaches, what the risks and rewards might be and how practical the scale-up would actually be.
Major challenges will be the low success rate of implantation procedures in higher level organisms, the ethical implications of putting human stem cells into animals at such early developmental stages, and (if whole organs are transplanted) whether an organ grown in another species could actually function in a human.
Before investing heavily into such approaches, these aspects of these potential technologies need to be considered and any trials moving forward should be highly scrutinized.
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