New way to grow iPS cell-derived kidney progenitor cells may lead to renal regenerative therapies

Professor Kenji Osafune (Department of Cell Growth and Differentiation) and his team of researchers have devised an effective means to grow iPS cell-derived kidney progenitor cells, paving the way for renal regenerative therapies to become a reality. The findings are published in the journal Science Translational Medicine.

Modern medicine continues to be hampered by the lack of effective treatments for acute kidney injury (AKI) and chronic kidney disease (CKD). Regenerative medicine, such as cell replacement therapies, represents a new hope for patients. Yet, such therapeutic approaches require large-scale production of the necessary cells, which had remained a challenge until this discovery.

Using a mouse model of AKI, the research team first demonstrated the therapeutic potential of human iPS cell-derived nephron progenitor cells (hiPSC-NPCs). When these cells were transplanted into the kidneys of AKI mouse models induced by an anti-cancer drug, cisplatin, the animals’ survival was vastly improved by preventing the deterioration of kidney function.

However, considering the difference in body size between mice and humans, a tremendous number of cells would be necessary if hiPSC-NPC transplantation is to become a realistic regenerative therapy for medical use in human patients. As such, the researchers returned to the drawing board and considered new ways to expand these cells in culture.

Instead of culturing the cells in a single layer in a traditional medium, by culturing them as clumps of cells in suspension in a medium that includes three chemicals known to influence kidney growth and development, the researchers found the cells to continue expressing protein markers characteristic of NPCs and retain their ability for continuous expansion. Following transplantation into mouse kidneys, they differentiated into different types of kidney cells, forming various parts of the organ.

The researchers noticed that the growth of these cell clumps depends heavily on the starting cell density, suggesting that the oxygen supply may be a limiting factor. Critically, they found cells expanded in this manner to possess similar therapeutic potential when transplanted into mouse models of AKI or CKD, indicating that they have found a way to greatly expand the cells necessary for cell therapies while maintaining their ability to function effectively once transplanted.

Furthermore, through detailed gene expression analysis, the research team identified a novel marker that could prove useful for purifying hiPSC-NPCs. To demonstrate the utility of this newly identified marker, they found that they could expand hiPSC-NPCs purified using this marker by 100 times simply over two passages.

In addition, they also discovered that hiPSC-NPCs produced VEGF-A—a secreted protein capable of inducing blood vessel formation and maintenance—and demonstrated that cells lacking the VEGFA gene had reduced therapeutic potential when transplanted into mouse models.

Through this study, the researchers, led by Professor Kenji Osafune, have developed a much-needed method to expand hiPSC-NPCs so they may be massively produced outside the body in the future for regenerative medicine purposes. By identifying a new marker for their purification and elucidating the principal mechanism underlying their therapeutic effects, the research team’s work enables the real-world application of hiPSC-NPCs as a potential treatment for AKI and CKD.