Chronic kidney disease (CKD), which affects an estimated 35 million people in the United States alone, represents a pervasive and growing health crisis. The condition often worsens over time, leaving patients more prone to strokes, heart attacks, and kidney failure. Dialysis takes a heavy personal and economic toll, while demand for transplants is far greater than the supply of available organs.
Benjamin Freedman, PhD is a UW associate professor of Medicine/Nephrology and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). For years, the Freedman Lab has been at the forefront of the effort to develop urgently needed new therapies that help heal sick kidneys by tapping into the body’s natural capacity for organ development and regeneration.
Specifically, Freedman and his team pioneered the use of induced pluripotent stem cells (iPSC) to grow kidney organoids – miniature three-dimensional structures that enable researchers to study how diseases develop in the kidney and to test potential drugs. However, these organoids do not have the full complexity needed for transplantation.
“Engineering a kidney outside the body is an extraordinarily tall order,” says Freedman. “Fortunately, we know that there are developmental stem cell pools that do this task in nature. Our question has been – can we take a short cut to grow enough healthy tissue to repair a damaged kidney while keeping the overall architecture of the existing organ?”
Evidence published in a new study from the Freedman Lab suggests the answer to that question might be, yes. The paper, which appears in the journal The Innovation, describes how stem cells were successfully tasked with the complex job of generating multiple cell types crucial for kidney function and demonstrated that it may be more efficient and effective to kickstart this process inside a patient’s kidney instead of engineering tissue outside the body for transplantation.
Freedman is the senior author of the study. The first author is Dr. Thomas Vincent, who recently completed his PhD in the Freedman Lab. Other authors include Dr. Samera Nademi, PhD, a postdoctoral fellow in the lab and collaborators at Sheba Medical Center in Tel Aviv, Israel.
According to Freedman, the first step in the process is to simultaneously, and organically, turn the induced pluripotent stem cells into two types of cells – tubule progenitor cells, which form structures important for filtering, balancing, and waste removal, and stromal progenitor cells, which ultimately provide supporting structure for the kidney. The researchers dubbed the resulting mix iMM, short for induced metanephric mesenchyme.
“It’s an elegant approach,” says Freedman. “Starting with the iPSC, it only takes a few days to derive the kidney stem cells that can make the tubule and stromal cells, which then go on to make many different cell types that self-assemble into this beautiful structure we recognize as kidney tissue. If we imagine someday being able to inject those starter cells into the body and letting them create the tissues in the places they have to be made, I think it’s a more direct route to actual healing.”
Notably, the stromal progenitors gave rise to mesangial cells, a specialized population that gives structure to kidney tissues. In previous implant studies, Freedman had never seen mesangial cells in the end-result specimens. This time, they were there, but only in grafts originating from the younger cell population, and not in grafts resulting from structures that been matured further before implantation.
At the heart of the study was a related question about the optimal timing for implanting cells into a host. Using a mouse model, they set out to determine whether it was better to inject the earlier pool of induced pluripotent stem cells before they differentiate into tubules and stroma or to let that transition happen before transplantation. The results showed it as unequivocally better to start with the stem cells.
Furthermore, they found that there is a window of opportunity for getting the cells into the body. Simply put, earlier is better. By comparison, organoids that were matured in the lab before transplantation fared more poorly and were likely to develop cysts. The younger cells of the iMM, meanwhile, survived and thrived, even forming vital connections with other components of the kidney like blood vessels that nourish the cells in the organ.
The next question, says Freedman, is how well the tissues that arise from the iMM can perform the functions of the kidney – in other words, whether they can rescue a damaged or dying kidney.
Another factor, of course, is safety. “We don’t want to transplant anything into a person that could cause additional problems. That’s going to require refining the timing and the location of implantation so that it’s properly tied into the vasculature and the excretory system that’s already there. If we can do that, I’m excited about the potential to heal kidneys, and other organs, and to help people who are running out of time and options.”
Acknowledgements
The work was supported by Cystinosis Research Foundation (CRFF-2021-003, CRFF-547-2023-004), National Institutes of Health (UC2DK126006), a Regular Award from the United States-Israel Binational Science Foundation, and an Institute for Stem Cell and Regenerative Medicine Fellows award.