Immunosuppression-free transplantation of autologous livers grown in xenogeneic species
Creating autologous livers from patients’ cells would solve many of the important issues connected to transplantation, including immunosuppression-related side effects and the shortage of donor. Because autologous transplantable livers would be a rapidly available resource, we would see the expansion of transplant for oncologic indications and pediatric patients would receive a transplant long before becoming too sick or developing irreversible impairments. Overall, the way we treat chronic organ impairment and end stage disease would be revolutionized, with invaluable benefit for our patients, their families and the health care system.

The dramatic advances in induced pluripotent stem cells (iPSCs) technology over the last few years are turning the idea of xeno-grown autologous (x-gA) livers into a tangible reality. The advent of blastocyst complementation with iPSCs allowed for the generation of interspecific chimeras with few human cells in pigs and mice, and the creation of mouse complete pancreatic parenchyma in a rat. In addition, our group successfully transplanted chimeric mouse/rat livers into rats and showed improved function and survival over classic mouse to rat xenotransplantation. This model proves the ability for recipient-oriented remodeling and suggests that the liver can grow far beyond the size limits of the species of origin.

The present project aims to establish fundamental concepts which will set the stage for human-oriented studies and clinical applications. In particular:

1) Establish immunosuppression-free long- term survival of rats transplanted with autologous livers generated in mice
2) To generate xenogeneic autologous human livers in mice

Desensitization by clonal deletion, to accept future xenogeneic grafts: towards a “Transplant Vaccine”
Exposing a species to xenogenic tissue during the pre-immune phase (in-utero) may induce tolerance to xenogeneic solid organ transplantation in adulthood. We know from our experience that mouse-rat chimeras generated by blastocyst complementation are keen to accept organs and tissues from the two species. The aim of this project is to develop a strategy to expose mice to rat tissue in utero and to compare the outcomes of kidney and skin xenotransplantation to the matching whole-body chimeras.

Passive isochoric sub-zero organ preservation
Transplantable organs are usually stored at 0-1 degrees Celsius. Lower temperatures determine the creation of ice crystals that compromise cellular integrity. Being able to extend the time an organ can be stored by lowering the temperature and, at the same time avoiding ice formation would facilitate long-distance transportation. Moreover, it would allow the creation of an organ bank, although short-term. With that in mind, we are designing and testing passive isochoric chambers that may allow organ preservation at sub-zero temperatures.

Implantable devices to reduce complications of pancreatic surgery
The leak of the pancreatico-jejunal (PJ) anastomosis or the pancreatic stump is a common complication that afflicts patients resected of the pancreas. Such complication entails longer hospital stays in the best case, but can also start a chain of events, sometimes leading to the patient's death (1-2%). Our group has designed and patented an implantable device that may significantly reduce the leak rate of PJ anastomoses. We are now working on producing the device with absorbable polymers, aiming at a pilot study in the next 1-2 years.