A Demonstration of Chimeric Tissue Farming: Mouse Pancreatic Tissue Grown in Rats

Today I noted the report of a proof of principle demonstration of the creation of chimeric animals that grow the organs of another species. This not the first such demonstration, but it is another step along the way to larger goals in tissue engineering. One of the potential approaches to building a large supply of new organs and tissues for transplantation is to grow humanized tissues in other species, such as pigs. This might be accomplished in many different ways, ranging from implanting seed cells or organoids into genetically altered adult animals, to creating engineered animal lineages in which all of the desired organs are at least partially humanized, compatible enough for xenotransplantation. That may involve as little as removing a few problem proteins in the case of porcine organs, but it remains to be seen how much concrete progress will be made by the current research programs with this specific focus. In the years ahead, this branch of technology will compete with therapies to regenerate organs in situ, as well as decellularization of donor organs, and efforts to grow or print suitable tissues for transplantation using only the patient's own cells as a starting point. It remains very unclear as to which of these approaches will prosper first.

Creating individual animals with one or more organs from another species requires some genetic engineering, to prevent the growth of the normal organ, followed by implantation of suitable seed cells in embryos early in the developmental process. If expanded into an industry, this methodology doesn't seem likely to result in a cost-effective supply of patient-matched tissues, given that it would require at minimum a few years to create a patient-matched organ for transplantation. It might, however, lead to multiple lines of animals, each possessed of humanized organs that can be transplanted, with little immunosuppression required, into one of the various human immunological groups. As is the case for many of the near future options for organ creation and xenotransplantation, this would be a great improvement over present shortages of donor organs, but it falls a long way short of the ideal future in which existing organs can be repaired and regenerated through some form of cell therapy or similar treatment.

Rat-grown mouse pancreases help reverse diabetes in mice

Growing organs from one species in the body of another may one day relieve transplant shortages. Now researchers show that islets from rat-grown mouse pancreases can reverse disease when transplanted into diabetic mice. The recipient animals required only days of immunosuppressive therapy to prevent rejection of the genetically matched organ rather than lifelong treatment. The success of the interspecies transplantation suggests that a similar technique could one day be used to generate matched, transplantable human organs in large animals like pigs and sheep.

To conduct the work, the researchers implanted mouse pluripotent stem cells, which can become any cell in the body, into early rat embryos. The rats had been genetically engineered to be unable to develop their own pancreas and were thus forced to rely on the mouse cells for the development of the organ. Once the rats were born and grown, the researchers transplanted the insulin-producing cells, which cluster together in groups called islets, from the rat-grown pancreases into mice genetically matched to the stem cells that formed the pancreas. These mice had been given a drug to cause them to develop diabetes.

The mouse pancreases were able to successfully regulate the rats' blood sugar levels, indicating they were functioning normally. Rejection of the mouse pancreases by the rats' immune systems was uncommon because the mouse cells were injected into the rat embryo prior to the development of immune tolerance, which is a period during development when the immune system is trained to recognize its own tissues as "self." Most of these mouse-derived organs grew to the size expected for a rat pancreas, rendering enough individual islets for transplantation. Next, the researchers transplanted 100 islets from the rat-grown pancreases back into mice with diabetes. Subsequently, these mice were able to successfully control their blood sugar levels for over 370 days, the researchers found. Because the transplanted islets contained some contaminating rat cells, the researchers treated each recipient mouse with immunosuppressive drugs for five days after transplant. After this time, however, the immunosuppression was stopped.

After about 10 months, the researchers removed the islets from a subset of the mice for inspection. "We examined them closely for the presence of any rat cells, but we found that the mouse's immune system had eliminated them. This is very promising for our hope to transplant human organs grown in animals because it suggests that any contaminating animal cells could be eliminated by the patient's immune system after transplant." Importantly, the researchers also did not see any signs of tumor formation or other abnormalities caused by the pluripotent mouse stem cells that formed the islets. Tumor formation is often a concern when pluripotent stem cells are used in an animal due to the cells' remarkable developmental plasticity. The researchers believe the lack of any signs of cancer is likely due to the fact that the mouse pluripotent stem cells were guided to generate a pancreas within the developing rat embryo, rather than coaxed to develop into islet cells in the laboratory. The researchers are working on similar animal-to-animal experiments to generate kidneys, livers and lungs.

Interspecies organogenesis generates autologous functional islets

Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse-rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.

Comments

"Creating individual animals with one or more organs from another species requires some genetic engineering, to prevent the growth of the normal organ, followed by implantation of suitable seed cells in embryos early in the developmental process. If expanded into an industry, this methodology doesn't seem likely to result in a cost-effective supply of patient-matched tissues, given that it would require at minimum a few years to create a patient-matched organ for transplantation."

Yes but people's organs often don't fail suddenly, so a few years wait might not be too much of a problem. So the market for patient matched organs grown in chimeric pigs could actually be quite large. Regarding cost effectiveness, the Australian government agreed to pay 250k per hepatitis C cure, because liver failure ends up costing the government around 1 million AUD per patient.

Also growing a fully human patient matched organ in a chimeric pig gets around the problem that we don't yet know how to print complex organs like kidneys. Maybe 3D printing will overcome this challenge in the near term, but maybe it won't. Having another approach of using a pig as a 3D printer is a welcome extra option.

Also this related paper, Interspecies Chimerism with Mammalian Pluripotent Stem Cells, came out today in which a human pig chimera was successfully created.

Paul Knoepfler's commentary on this: http://www.ipscell.com/2017/01/perspective-on-pig-human-chimera-paper/

Posted by: Jim at January 26th, 2017 8:47 PM

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