More than 50,000 people in the United States alone are on the waiting list for kidney transplants. The wait can last years – and steadily claim victims along the way.
A landmark study recently reported in Nature Medicine now offers hope of a future solution. Prof. Yair Reisner of the Weizmann Institute of Science has succeeded in growing miniature human kidneys in mice, using human stem cells. His team has also produced pig kidneys in mice, using the same technique. The kidneys were fully functional.
Reisner and Ph.D. student Benny Dekel of the Weizmann Institute’s Immunology Department, with Prof. Justen Passwell, who heads the pediatric department at Tel Aviv’s Sheba Medical Center, transplanted human and pig kidney precursor cells (stem cells destined to become kidney cells) into mice. Both the human and pig tissue grew into perfect mouse-size kidneys. The miniature kidneys were functional, producing urine. In addition, the risk of rejection – a common phenomenon in current transplantation procedures – was greatly reduced, since blood supply within the kidney was provided by host rather than donor blood vessels.
“The findings suggest that one day it might be possible to grow a healthy kidney in a human by transplanting human or pig fetal tissue into the patient,” says Reisner.
Window of opportunity
To date, the key obstacle to transplanting embryonic stem cells from one kind of animal into another has been that of timing: Cells that were too old suffered substantial immune rejection, while cells that were too young were found to develop into disorganized tissue that included non-kidney structures, such as bone, cartilage and muscle.
The Institute team succeeded in pinpointing the ideal time during embryonic development at which stem cells have the best chance of forming well-functioning kidneys with a minimal risk of rejection: 7- to 8-week-old human tissue and 4-week-old porcine tissue were found to offer the optimal window of opportunity for transplantation. Within this time range the tissue lacks certain cells that the body recognizes as foreign.
To determine whether the immune system would reject human and pig kidneys grown in mice, the scientists grew the kidneys in mice that lack an immune system. They then restored the animals’ immunity by injecting human immune cells called lymphocytes. Their findings were encouraging: As long as the kidney stem cells were transplanted at the right stage, the lymphocytes did not attack the new pig or human kidneys. Rejection rates in normal (immune-functioning) mice were also reduced compared to those caused by older stem cells. “If all goes well, we hope to begin human trials within a few years,” says Reisner.
The challenge of stem cell therapy
The current accomplishment of growing functional kidneys in mice using human stem cells marks yet another milestone in the career of Prof. Yair Reisner, whose prize-winning stem cell research has spanned more than 20 years.
Stem cells in bone marrow (the sponge-like tissue found in the center of certain bones) are the precursors of red and white blood cells. They play a crucial role in transplant therapies aimed at saving the lives of people with acute leukemia and other blood disorders.
The strategy, however, depends on finding a compatible donor. Patients lacking a suitable donor among their siblings have to search the general population, and many fail to find one, even though donor registries – which include more than 8 million volunteers – have been established worldwide.
Collaborating with a team led by Prof. Massimo Martelli of Italy’s Perugia University, Reisner has made it possible to transplant even partially matched stem cells in leukemia patients. Nearly 400 patients throughout Europe have been treated using the new approach, yielding significant success rates, as reported in the New England Journal of Medicine, Science and other leading journals. Reisner and Martelli recently received the Daniele Chianelli Prize for their work.
The first mismatched transplant using the Reisner-Martelli approach was attempted in 1993, in a 20-year-old factory worker from Italy who had no matched donor in his family. As there was no time to search for an unrelated donor, physicians intended to perform an autologous transplant (using the patient’s own stem cells), but before the transplant was ready, the patient’s disease had progressed to a critical stage. At the family’s request, the Perugia team attempted their new approach, using the patient’s father as a partially matching donor.
Following a successful recovery, the patient was able to resume his normal lifestyle and return to his job at the factory, where he still works today.
Prof. Yair Reisner is the incumbent of the Henry H. Drake Professorial Chair in Immunology. His research is supported by Richard M. Beleson, San Francisco, CA; Renee Companez, Australia; the Concern Foundation; the Crown Endowment Fund for Immuno-logical Research; Erica A. Drake, Scarsdale, NY; Robert Drake, the Netherlands; the Ligue Nationale Francaise Contre le Cancer; the M.D. Moross Institute for Cancer Research; the Gabrielle Rich Leukemia Research Foundation; Rowland Schaefer, Pembroke Pines, FL; and the Union Bank of Switzerland-Optimus Foundation.