Two new USC studies unveil a blueprint that makes it possible to generate specific kidney cell types on demand—cells that hold immense value for preclinical studies of new therapeutics, congenital kidney diseases, and drug-induced nephrotoxicity. In the first study, using organoids containing hundreds of nephron-like structures, the team identified a “switch” that directs precursor cells toward either a proximal or distal identity. To form distal nephron cells the scientists modulated key molecular signals or “pathways” known to drive embryonic development and the differentiation of stem cells into more specialized cell types, among other biological processes. Specifically, they suppressed the cell-to-cell signaling pathway BMP, activated the WNT pathway, and switched on the FGF pathway. If they switched off FGF, the cells reverted to a proximal identity and would eventually start to mature into filtration and absorption structures, including podocytes and early-stage proximal tubules. In another study the team discovered that the lab-grown versions of nephron cells failed to fully mature because they lacked normal signals that control how the nephron’s proximal-to-distal axis forms, which is essential for well-organized proximal tubules. They found that nephron cells could be encouraged to adopt a proximal tubule identity by tweaking cell signaling. Researchers then tested the lab-grown proximal tubule cells and found these lab-grown cells formed organoids that absorbed sugar (dextran) and protein (albumin), and responded to the chemotherapy drug cisplatin by showing drug-induced injury—recapitulating the behavior of human kidneys. Finally, the organoids also produce transporters, which are proteins that move molecules or drugs across membranes and enable a proximal tubule to function—something that has been missing for the field and for the pharmaceutical industry.
