Induced Pluripotent Stem Cell-Derived Kidney Progenitor Cells Heal Kidneys in Laboratory Animals


The kidney is a crucial organ for human survival and human flourishing. This organ filters metabolic wastes from the blood and if the kidney does not work, the body slowly poisons itself.

When the kidneys fail to work properly, they must be replaced by transplantation of a tissue-matched kidney from a donor. However, if the kidney is not completely damaged, then it might be possible to heal it by means of cell therapies. For example, if we could transplant renal progenitor cells into the kidney that then differentiate into kidney-specific tissues, then we could potentially replace damaged tissues in the kidney and help the kidney fully recover. The tough part of such a treatment strategy has been acquiring a sufficient number of kidney progenitor cells. However, scientists have considered using induced pluripotent stem cells (iPSCs), since these cells can be expanded in culture to very high numbers of cells that can be effectively differentiated into kidney progenitors.

Induced pluripotent stem cells are made from mature, adult cells by means of a combination of genetic engineering and cell culture techniques. These cells have the potency to differentiate into any cell type in the human body. Ideally, renal progenitors could be transplanted directly into the kidney parenchyma, but, again, this is not a simple-to-solve problem. “The kidney is a very solid organ, which makes it very difficult to bring enough number of cells upon transplantation,” explains Professor Kenji Osafune. Dr. Osafune’s laboratory is at the Center for iPS Cell Research and Application (CiRA) at Kyoto University, Japan, and is using iPSCs to investigate new treatments for kidney disease. Several studies have successfully transplanted adequate numbers of kidney progenitors to treat kidney disease.

In a new study, Dr. Osafune has collaborated with Astellas Pharma Inc., in order to potentially design a solution that can solve the problem of treating the kidney with exogenous cells. In this study, Osafune and his colleagues tried a different way to deliver the kidney progenitor cells. Instead of injecting cells directly into the kidney, they transplanted their iPSC-derived renal progenitors into the kidney subcapsule that is at the kidney surface.

Kidney Capsule

The mice that received the cells were suffering from acute kidney injury. Even though the transplanted cells never integrated with the host, mice that received this transplant showed better recovery, including less cell death (necrosis) and scarring (fibrosis) compared with mice that received transplants of other cell types.

Damaged kidney tissue (left) of an AKI model mouse shows high levels of fibrosis (blue). Treatment with Osr1+Six2+ cell therapy significantly ameliorates the fibrosis (right) of another AKI model mouse.
Damaged kidney tissue (left) of an AKI model mouse shows high levels of fibrosis (blue). Treatment with Osr1+Six2+ cell therapy significantly ameliorates the fibrosis (right) of another AKI model mouse.

Osafune attributed the improvement in his laboratory mice to the use of cells that expressed the Osr1 and Six2 genes. The Osr1 and Six2 proteins are known markers of renal progenitor cells, but until this particular study, researchers had not exclusively used cells that expressed both of these proteins for cell therapies.

Kidney Progenitor cells

Another conclusion from the study was that because the cells did not integrate into the kidney, their therapeutic effects were the result of secreted proteins that promoted kidney healing and protection. While most stem cell therapies aim for integration of the transplanted cells, the results of these experiments could have important clinical implications. In particular, this experiment is one of the first to show the benefits of using human iPS cell-derived renal lineage cells for cell therapy. Secondly, scarring of the kidney is a marker that indicated progression of the kidney to chronic kidney disease. Since scarring was significantly reduced in these experiments, these data suggest that the paracrine effects of the transplanted cells could act as preventative therapy for other serious ailments. Finally, Osafune believes these effects could provide valuable clues for drug discovery. “There is no medication for acute kidney injury. If we can identify the paracrine factor, maybe it will lead to a drug.”

From:  Takafumi Toyohara, et al., “Cell therapy using human induced pluripotent stem cell-derived renal progenitors ameliorates acute kidney injury in mice” Stem Cells Translational Medicine.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).