Regeneration and experimental orthotopic transplantation of a bioengineered kidney

ORIGINAL: Nature

Jeremy J Song, Jacques P Guyette, Sarah E Gilpin, Gabriel Gonzalez, Joseph P Vacanti &Harald C Ott

14 April 2013

Nature Medicine 19, 646–651 (2013)

doi:10.1038/nm.3154

Received 04 September 2012

Accepted 11 February 2013

Published online 14 April 2013

Approximately 100,000 individuals in the United States currently await kidney transplantation, and 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidney function would address donor organ shortage and the morbidity associated with immunosuppression. Such a bioengineered graft must have the kidney's architecture and function and permit perfusion, filtration, secretion, absorption and drainage of urine. We decellularized rat, porcine and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, a collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells and perfused these cell-seeded constructs in a whole-organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused through their intrinsic vascular bed. When transplanted in an orthotopic position in rat, the grafts were perfused by the recipient's circulation and produced urine through the ureteral conduit in vivo.

Figure 1: Perfusion decellularization of whole rat kidneys. (a) Time-lapse photographs of a cadaveric rat kidney undergoing antegrade renal arterial perfusion decellularization. Shown are a freshly isolated kidney (left) and the same kidney after 6 h (middle) and 12 h (right) of SDS perfusion.

Figure 2: Perfusion decellularization of porcine and human kidneys.(a) Photograph of cadaveric (left) and decellularized (right) porcine kidneys suggesting that perfusion decellularization of rat kidneys can be upscaled to generate acellular kidney ECMs of clinically relevant size. Ra, renal artery; 

Figure 3: Cell seeding and whole-organ culture of decellularized rat kidneys. (a) Schematic of a cell-seeding apparatus enabling endothelial cell seeding through port A attached to the renal artery (Ra) and epithelial cell seeding through port B attached to the ureter (U) while negative pressure in the organ cham…

Japan researchers say kidney tissue grown from stem cells (Update)

ORIGINAL: MedicalXpress

by Harumi Ozawa in Medical research

January 23, 2013 

A scientist is pictured on August 27, 2010 working on stem cells in a laboratory. Researchers in Japan said Wednesday they have succeeded in growing human kidney tissue from stem cells for the first time in a potential breakthrough for millions with damaged organs who are dependent on dialysis.

Researchers in Japan said Wednesday they have succeeded in growing human kidney tissue from stem cells for the first time, in a potential first step towards helping millions who depend on dialysis. 

Kidneys have a complex structure that is not easily repaired, but the latest findings put scientists on the road to fixing a diseased or distressed organ, they said.

More than 300,000 people in Japan alone rely on dialysis because their kidneys do not function properly. Researchers said the latest breakthrough may one day mean that kidney tissue generated from a patient's own body could markedly improve how a damaged organ works.

Kenji Osafune of Kyoto University said his team had managed to take stem cells—the "blank slates" capable of being programmed to become any kind of cell in the body—and nudge them specifically in the direction of kidney tissue.

"It was a very significant step," he told AFP.

Osafune said they had succeeded in generating intermediate mesoderm tissue from the stem cells, a middle point between the blank slate and the finished kidney tissue.

"There are about 200 types of cells in the human body, but this tissue grows into only three types of cells," namely adrenal cells, reproductive gland cells and kidney cells, he said, adding that as much as 90 percent of cultures in their research developed into viable mesoderm tissue.

This embryonic intermediary can be grown either in test tubes or in a living host into specific kidney cells.

Osafune stressed there are still many hurdles to overcome before applying his work to actual medical treatment. "It is not known yet if simply transplanting regenerated cells would really cure kidney ailment," he said.

He and his team created part of a urinary tubule, a small tube in the kidney that plays a role in the production of urine.

While the research is not aimed at growing an entire working kidney, he said the method his team had developed would help scientists learn more about intermediate mesoderm development and may provide a source of cells for regenerative therapy.

"I would say that we have arrived at the preliminary step on the road to the clinical level," he said.

Stem cell work has been controversial until relatively recently because embryos were the only source, and their harvesting led to the destruction of what some people consider a human life.

This research has used induced Pluripotent Stem (iPS) cells, a bio-technology where a fully-developed adult cell is effectively re-engineered to return it to its infant state.

Last year Shinya Yamanaka, director of the Centre for iPS Cell Research and Application of which Osafune is a part, was a co-recipient of the Nobel Prize for medicine for his pioneering work on the iPS cells.

Yamanaka and Britain's John Gurdon were jointly honoured for work on the key ingredient in the vision of regenerative medicine.

Work involving iPS cells is seen as a way scientists can generate materials either to experiment on, or to use within the body—perhaps as a means of repairing or even replacing damaged or diseased organs.

Osafune's achivement, while significant, brings researchers effectively to the foot of a mountain they must climb if they want to grow a working kidney, warned Takahashi Yokoo, lecturer at Jikei University School of Medicine in Tokyo.

"Yes, a tubule structure was generated, but an enormous amount of research is still necessary to create an orderly structure that produces urine," Yokoo, a kidney expert not involved with Osafune's study, told AFP.

"We must refrain from hyping optimism among patients because to do so is to ignore the most difficult part of the efforts to create kidneys." 

"We are hopeful about the latest achievement. This study puts us at the starting line for a big mission ahead."

Osafune's research is published in online science journal Nature Communications.

Journal reference: Nature Communications

(c) 2013 AFP