MDI Bio Lab scientists discover how the fish solves a basic challenge in regenerative biology—insights in their newest publication in the journal Development could one day guide human repair.
When the human kidney is damaged by conditions such as high blood pressure or the elevated blood sugar levels that accompany diabetes, it can lose some of its nephrons – the kidney's basic waste-filtering units.
Lose enough of them and kidney function falters, leading to the hallmarks of chronic kidney disease: fatigue, swelling, shortness of breath. It's the ninth leading cause of death in the world.
And in adult humans, once a nephron is gone, it's gone. There is no way to grow it back.
At least, not yet.
Scientists at MDI Bio Lab and around the world are attacking the problem from many angles; growing new kidney tissue and mini-organs called "organoids" from human stem cells, using 3D "bioprinting" to build a new kidney from scratch, or coaxing the body to repair and regenerate its own nephrons and kidneys, the way some other animals do.
Such as the zebrafish.
A Fish That Can Replace What We Cannot
Unlike humans, adult zebrafish can form entirely new nephrons after kidney injury. Even more remarkable, those new filtration units don't simply grow; they connect themselves to a network of microscopic pipes (called tubules) that flow fluid through the kidneys, retaining water, electrolytes and nutrients while shunting waste products into the urinary system.
Scientists have had some success generating kidney tissue in the lab, and even grafting it into mammals such as mice. But getting a kidney organoid to hook into the tubule network and actually perform its filtering functions? Not so easy.
"It's a plumbing problem," says Iain Drummond, Ph.D., Scientific Director of MDI Bio Lab's Kathryn W. Davis Center for Regenerative Biology and Aging.
"It's one thing to grow kidney tissue in a Petri dish," he continues. "It's another to integrate that tissue into a working organ — to link new plumbing into old pipes and send fluid through without leaks, or blockages, or wrong turns."
Connecting New Pipes to Old
Drummond, MDI Bio Lab Senior Research Scientist Caramai Kamei, Ph.D., and their colleagues set out to discover how zebrafish solve the problem .
"We knew new nephrons were forming," Kamei explains. "But nobody had looked closely at how they physically hook up to the existing tubule."
What the team discovered was a highly coordinated cellular choreography: At the precise point where a newly forming zebrafish nephron meets an older kidney tubule, a small group of cells briefly changes its behavior.
Instead of remaining in compact rows, these cells extend protrusions into the neighboring tissue, helping initiate the connection between old and new structures.(The MDI team and research collaborators are the first to fully describe these protrusions and their function).
Just one cell's distance away, other cells are doing something entirely different, dividing and contributing to the growth of the newly forming tubule. Farther from the connection site, cells begin differentiating into the structures needed for filtration. Side by side, one population invades and connects, while another builds and specializes.
"It's one cell apart," Kamei says. "One cell is doing one thing, and the next is doing something different."
Guiding the Connection
The study found that this plumbing process is governed by intersecting signaling systems, including a well-studied protein cascade deployed in many species, including humans, called the "canonical" Wnt pathway.
The researchers also found a second branch of the Wnt messaging system that depends on a cell-surface "switch" called fzd9b that helps cells orient the connection so that the new unit links up in the right place and direction.
Together, these molecular cues tell cells when to grow, when to change shape, and when to stop dividing and focus on integration, while guiding where the connection forms. If all goes well the result is a functional, open junction between old and new, an integrated filtering unit that can drain into the kidney's plumbing system.
It Has to Work
Drummond believes the importance of the zebrafish's reconnection technique reaches well beyond the kidney. That's because in regenerative medicine, growing a wide variety of tissue types in a laboratory is no longer the central obstacle; engrafting that tissue inside a living system and having it actually work remains the greater challenge, and a potential bottleneck for the field's development.
"At some point," Drummond says, "you don't just want tissue sitting there. It has to do something. The plumbing has to go somewhere."
From a basic biological point of view, many researchers also believe that the onset of function helps drive final maturation of a new organ and may be required for true success. "The moment that fluid starts flowing through a tube or blood begins circulating through new vessels, cells respond," Drummond says. "They change. They stabilize."
Without that final step, lab-grown tissues may resemble organs structurally, but still never achieve the durability and functionality of the real thing, he says. If scientists can learn from the zebrafish how to guide new, human kidney tissue or other engineered organs to integrate and begin functioning in the body, the implications extend across regenerative biology.
"That's the final step that's missing with a lot of these lab-grown, tissue-based organs," Drummond says. "We have our eyes open for that, and I'm hopeful we'll have an impact on making stem-cell–derived tissues not just structurally correct, but functionally useful."
That shift — from constructing tissue to restoring performance — represents one of the central challenges of regenerative medicine today.
