20 December 2017

Artificial kidney – a matter of time

Worldwide, more than 2 million people suffer from chronic kidney failure. Some of them are forced to undergo hemodialysis several times a week for life. A kidney transplant is a more advantageous option, but not everyone can wait for a transplant. In 2006, Japanese scientists began work on growing a kidney from stem cells.

There are three types of progenitor cells in the embryonic kidney: nephron precursors, ureteral rudiments, and interstitial progenitor cells. Interacting, they form a three-dimensional structure of the kidney.

Methods of inducing nephron progenitor cells from pluripotent stem cells (PSCs) in mice were previously known, but since other progenitor cells were not involved, it was not possible to obtain a kidney with a higher-order structure when the nephron is organically connected to all structures.

A research team from the Institute of Molecular Embryology and Genetics at Kumamoto University has developed a way to use UCS to form a ureteral germ, from which collecting tubes are then formed.

Previous studies have shown that the interaction of three types of progenitor cells plays an important role for the embryonic development of the kidney. Ureteral rudiments are of great importance, since it is from them that collecting tubes are formed. Interstitial progenitor cells form tissue that fills the space between the nephrons and the network of tubules and tubes.

At the end of 2013, the research team developed a method for inducing nephron progenitor cells from mouse embryonic stem cells (ESCs) and human induced stem cells. They managed to create a three-dimensional kidney structure containing a nephron. But it has not been possible to "grow" a tubular network from progenitor cells until today.

Tubules and tubes collect urine, which is formed in the nephron, and remove it into the pelvis to the ureter, from where it should enter the bladder, and then be excreted from the body.

The researchers focused on developing a method for inducing ureteral rudiments from UCS and creating a kidney by combining UCS-derived nephrons and embryonic progenitor stem cells.


On the left: a highly organized kidney structure created from mouse ESCs; weak magnification. The collecting tubes are indicated in green, and the progenitor cells of the nephron are indicated in red. Right: nephron connected to the end of the collecting tube; strong magnification. The collecting tubes are indicated in green, the distal convoluted tubule in red, the proximal convoluted tubule in blue, and the glomerulus in pink. Here and below are the drawings from the Kumamoto University press release.

They found for the first time that mouse Wolf ducts (VP), from which ureteral rudiments are formed, gradually matured and acquired the ability to branch on the 8th-11th day of embryogenesis. The researchers cultured VP cells in vitro and identified the growth factors needed to produce ureteral rudiments. Finally, they developed a protocol for inducing ureteral rudiments from mouse ESCs using VP cells. It turned out that the progenitor cells of the nephron and the ureteral rudiments require completely different conditions for development.


Above: the process of morphogenesis of the kidneys of a mouse embryo. Below: nephron precursors created from UCS without ureteral rudiments and interstitial cells.

The functionality of ureteral rudiments from mouse ESCs was further tested by co-culturing one rudiment with kidney ESCs, and then in combination with ESCs-derived nephron precursors and embryonic stromal precursors. In such a reconstruction of the kidney, scientists observed branching of the ureteral epithelium, differentiation of nephrons and nephron precursors on the surface of the ureteral rudiments. This confirmed the functionality of the induced ureteral rudiments and the possibility of creating a kidney structure.

By making small changes to the protocol, the researchers were able to create ureteral rudiments from induced human UCS and demonstrated their ability to branch when cultured in the presence of growth factors.

Creation of a highly organized kidney structure from UCS.

The researchers conducted a similar experiment with induced human UCS with depletion of the PAX2 gene. This gene is known to be necessary for kidney formation in mice and in humans. In such conditions, ureteral rudiments were not formed, their branching was not observed. Thus, the ureteral rudiments obtained from induced UCS can be used to study abnormalities of kidney development caused by a gene mutation.

The results of the study demonstrate the possibility of reconstructing the complex structure of the kidney from induced UCS. Using the created protocol, it is possible to induce and combine different types of progenitor cells in accordance with individual development processes. This work provides the fundamental foundations for kidney regeneration and the study of the mechanisms of organogenesis.

There is still a lot of work to be done to create an artificial kidney from UCS. It is necessary to recreate interstitial tissue from progenitor cells. In addition, blood vessels are necessary for proper growth and normal functioning of the organ.

Thus, it is still far from growing a full-fledged kidney from stem cells, but the development of the authors of the study to create a network of collecting tubules and tubes is certainly another important step in this direction.

Article by Atsuhiro Taguchi et al. Higher-Order Kidney Organogenesis from Pluripotent Stem Cells is published in the journal Cell Stem Cell.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of EurikAlert: Reproducing higher-order embryonic kidney structures using pluripotent stem cells.

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