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Human stem cell-derived kidneys connect to blood vessels when transplanted into mice.

In the field of iPS cell-based regenerative medicine, advanced research with clinical applications for many organs and tissues, such as the retina, has steadily progressed. However, growing a kidney from scratch has been extremely difficult.  Although the number of renal failure patients on dialysis is increasing, opportunities for renal transplant have been limited with great attention given to the growth of kidneys to stem the shortage.

Now, a study from researchers at Kumamoto University shows mouse kidney capillaries successfully connecting to kidney tissue derived from human iPS cells. The team state that this achievement shows that human kidney glomeruli made in vitro can connect to blood vessels after transplantation and grow to maturity, a big step forward in gain-of-function for a urine-producing kidney.  The opensource study is published in the Journal of the American Society of Nephrology.

Earlier studies from the lab led to the development of an in vitro three-dimensional kidney structure from human iPS cells.  However, it was unclear how similar the kidney tissue made in vitro was to that formed in a living body. Additionally, the original kidney tissue was not connected to any blood vessels, even though the primary function of the organ is to filter waste products and excess fluid from the blood.  In many kidney diseases, the pathology is with the glomeruli that filter urine from the blood. Filtration in the glomerulus is performed by cells called podocytes that are in direct contact with the blood vessels. Through the special filtration membrane of the podocytes, proteins don’t leak into the urine and allows moisture to pass through.  Therefore, the group focused on analyzing the podocyte of the glomeruli in detail.  They achieved this by genetically modifying the iPS cells and growing human kidney tissue in vitro with green fluorescence then visualizing how human glomeruli became established.

The current study continued this analysis by taking out only the podocytes of the human glomeruli using the green fluorescence, and revealed that glomerular podocytes made in vitro express the same genes important for normal biological function.  Data findings show that after transplanting the human iPS cell-based kidney tissue into a mouse body, glomeruli connecting to mouse kidney capillaries formed. Results show that human glomerular podocytes further matured around adjacent blood vessels as in a living body and formed a characteristic filtration membrane structure.  The group state that to their knowledge the successful connection of capillaries with the podocytes of iPS cell-manufactured human glomeruli resulting in a distinct filtration membrane is the first of its kind in the world.

The team surmise that their findings should advance research into the manufactured kidney’s function to produce and excrete urine.  They go on to add that by using iPS cells from patients, development of new drugs and clarification of the causes of kidney disease are also expected.  For the future, the researchers state that they are now working to develop a discharge path for the kidney and combine it with findings on glomerular cells.

Source: The Institute of Molecular Embryology and Genetics (IMEG)

The kidney tissues derived from human iPS cells A.The kidney tissue generated in vitro, which shows green fluorescence in each glomerulus. B.Vascularized glomerulus formed upon transplantation into the mouse. Many red blood cells (arrowhead) are observed, and the substance exists in the lumen (*), suggesting the possible filtration. C.Mouse vascular endothelial cells (green) are incorporated into the glomerulus that consists of podocytes (magenta). D.The slit diaphragm (arrow) formed between the cellular processes of the podocytes. Credit: The Institute of Molecular Embryology and Genetics (IMEG).
The kidney tissues derived from human iPS cells
A.The kidney tissue generated in vitro, which shows green fluorescence in each glomerulus.
B.Vascularized glomerulus formed upon transplantation into the mouse. Many red blood cells (arrowhead) are observed, and the substance exists in the lumen (*), suggesting the possible filtration.
C.Mouse vascular endothelial cells (green) are incorporated into the glomerulus that consists of podocytes (magenta).
D.The slit diaphragm (arrow) formed between the cellular processes of the podocytes. Credit: The Institute of Molecular Embryology and Genetics (IMEG).

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