Scientists in Japan say they have made a critical step forward in kidney regeneration. A team from Hiroshima University, Kumamoto University, and Juntendo University School of Medicine have shown that mouse kidney capillaries can successfully connect to kidney tissue that was derived from human induced pluripotent stem (iPS cells). In essence, the group’s work demonstrates that human kidney glomeruli made in vitro can connect to blood vessels after transplantation and grow to maturity. The team views their research study (“Human Induced Pluripotent Stem Cell-Derived Podocytes Matue into Vascularized Glomeruli upon Experimental Transplantation”), published in the Journal of the American Society of Nephrology, as a huge step forward in gain-of-function for a urine-producing kidney.
According to the scientists, advanced iPS research with clinical applications for many organs and tissues, such as the retina, has progressed. Creating a kidney, however, has been extremely problematic. Although the number of renal failure patients on dialysis has been increasing, opportunities for renal transplant have been limited. Investigators at Kumamoto University have been researching the issue since 2006 with the goal of building a functioning kidney in test tubes. At the end of 2013, they reported in Cell Stem Cell the successful creation of an in vitro three-dimensional kidney structure from human iPS cells (“Redefining the In Vivo Origin of Metanephric Nephron Progenitors Enables Generation of Complex Kidney Structures from Pluripotent Stem Cells”).
Yet, it remained to be determined 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 trouble is with the glomeruli that filter urine from the blood. Filtration in the glomerulus is performed by “podocytes that are in direct contact with the blood vessels. Through the special filtration membrane of the podocytes, protein does not leak into the urine but allows moisture pass through.
“Therefore, we focused on analyzing the podocyte of the glomeruli in detail,” said Ryuichi Nishinakamura, M.D., Ph.D., a professor in the division of integrative cell biology in the institute of molecular embryology and genetics at Kumamoto University and who led the research. “First, by genetically modifying the iPS cells, we created human kidney tissue in vitro with green fluorescence. Then, we visualized how human glomeruli become established.”
The scientists continued the 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. After transplanting the human iPS cell-based kidney tissue into a mouse body, glomeruli connecting to mouse kidney capillaries formed. Human glomerular podocytes further matured around adjacent blood vessels as in a living body and formed a characteristic filtration membrane structure.
“Therefore, the podocytes generated from iPS cells retain the podocyte-specific molecular and structural features, which will be useful for dissecting human glomerular development and illnesses,” wrote the researchers in the Journal of the American Society of Nephrology paper.
This report of 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, added Dr. Nishinakamura.
“We are now working to create a discharge path for the kidney and combine it with our findings on glomerular cells. We hope to advance manufactured kidney gain-of-function to produce and excrete urine,” he continued. “Also, by using iPS cells from patients, development of new drugs and clarification of the causes of kidney disease are also expected.”