Japanese and Australian researchers have used induced pluripotent stem cell (iPSC) technology to reprogram human skin cells to make the most mature human kidneys yet to be grown in a culture. These mini kidneys have hundreds of filtering units (nephrons) and blood vessels and appear to be developing just as kidneys would in an embryo.
“The short-term goal is to actually use this method to make little replicas of the developing kidney and use that to test whether drugs are toxic to the kidney,” said lead researcher Professor Melissa Little, of the Murdoch Children’s Research Institute. “Ultimately we hope we might be able to scale this up so we can … maybe bioengineer an entire organ.”
In other previous research, Professor Little and her co-workers generated cells that self-organized into the nephrons and collecting ducts needed for the kidney to filter blood and produce urine. They used a precise combination of called growth factors to direct embryonic stem cells to develop into the different cell types.
In the journal Nature, Professor Little and her collaborators report they have made a developing kidney from a type of skin cell called a fibroblast. Little and her team reprogrammed adult fibroblasts to become “induced pluripotent stem cells,” which act like embryonic stem cells, and can become any cell in the body. By adopting their growth factor recipe, Little and others were able to grow these cells into larger and more complex, three-dimensional kidneys than previously made.
“These kidneys have something like 10 or 12 different cell types in them … all from the one starting stem cell,” said Professor Little. “What we had previously were little flat structures over the surface of a dish … Now we have an organoid that is about 5-6 millimetres across, has about 100 filtering units in it, and is starting to form blood vessels. It’s starting to mature and the cell types are starting to do more of the functions of the final kidney.”
Scientists in Little’s laboratory demonstrated that the genes expressed in the mini kidneys as they formed faithfully recapitulated the expression of those same genes in a developing kidney in a first trimester embryo.
“It is actually mirroring what is happening in human development,” said Professor Little.
Little and her group also found that the laboratory-grown kidney was damaged when it was treated with known renal toxins. Little suggested that the iPSCs cells they had created were functioning as a kidney, but further tests would be required to demonstrate that.
It might be possible to use these bioengineered kidneys to test the renal toxicity of drugs. Likewise, the production of mini kidneys using cells from kidney patients might provide a way to study inherited forms of kidney disease.
“You can take a fibroblast [from someone with inherited kidney disease], make a stem cell out of it, generate a little kidney and use that as our model for their disease,” said Professor Little.
Perhaps most exciting, laboratory-generated kidneys might one day provide rejection-free transplants for patients, and gene editing could be used to fix the genetic defect that caused an inherited kidney disease.
Professor Jamie Davies of the University of Edinburgh, who was not involved with this work, but commented on it for Nature, emphasized this was not a full-fledged, functional kidney. “The structure’s fine-scale tissue organization is realistic, but it does not adopt the macro-scale organization of a whole kidney. For example, it is not ‘plumbed’ into a waste drain, and it lacks large-scale features that are crucial for kidney function, such as a urine-concentrating medulla region. There is a long way to go until clinically useful transplantable kidneys can be engineered, but [this] protocol is a valuable step in the right direction.”
Davies also mentioned that these mini kidneys had the potential to replace “poorly predictive” animal drug safety tests, and called on researchers to team up with toxicologists to test the potential of their system.