Regeneration is, of course, the Holy Grail of medicine. Many diseases are chronic because they are a consequence of damage to organs or tissues beyond any natural repair mechanism. When kidneys are damaged beyond repair, the only answer may be transplantation (severely restricted due to the scarcity of donors) or dialysis – a terrible burden on patients (over 350,000 in the U.S.) who are forever tethered to their condition by weekly and sometimes daily visits to a machine. Harnessing the power of the kidney’s innate ability to regenerate could enable patients to regain their health.
“The kidney actually ranks very highly in its ability to repair itself,” said Joseph Bonventre, MD, PhD Professor of Medicine at Harvard Medical School, Chief of the Renal Division at Brigham and Women’s Hospital, and head of the HSCI Kidney Disease Program.
Bonventre and his team study the mechanisms by which the kidney repairs tissue after disease, particularly the repair of nephrons, which are the key functional units of the kidney. The nephron consists of a filtering unit for the blood, the glomerulus, and a complex tubule responsible for filtering the blood. The small tubules collect the filtrate and process it before passing it on to ducts leading to the bladder. “If tubules are damaged they can be repaired but if the damage is severe enough the nephron may be destroyed. Unfortunately the kidney can regenerate and recover, but the kidney cannot make new nephrons, and in that context, its regeneration is limited.”
What happens to the tubules is a clinically relevant question. In kidney disease, whether the disease starts in the filters or the tubules, the tubules ultimately become involved as they are highly susceptible to injury. A reduction in blood flow can lead to a restriction in the supply of oxygen, which can be lethal to the epithelial cells that form the lining of the tubules. For acute kidney injury, the tubules are often (but not always) capable of recovering completely. In chronic kidney failure, the injuries are progressive and nephrons are lost.
Many theories exist on kidney repair. Some suggest that the kidney may recruit circulating stem cells to migrate into and regenerate the damaged area, others that local tissue specific stem cells may be triggered to differentiate and rebuild, and still others that the kidney may forego a direct role for stem cells altogether by inducing mature cells to proliferate.However, a recent study by Bonventre, HSCI Affiliated Faculty member Benjamin Humphreys, MD, PhD, HSCI Executive Committee Member Andrew McMahon, PhD, and their team went a long way toward understanding how the tubules repair themselves.
By tagging the mature epithelial cells that form the tubule walls with a red fluorescent protein, the HSCI team was able to demonstrate that the replacement cells after injury are coming from the epithelium itself rather than from circulating stem cells that enter the kidney or local tissue specific stem cells in the tissue between the tubules. These stem cells might not be sitting on the sidelines, however. Other evidence suggests that they may be offering some assistance in causing the epithelial cells to multiply.
“The Harvard Stem Cell Institute basically has allowed us to look at kidney disease in a different and, in many cases, quite definitive way.”
– Joseph Bonventre, MD, PhD
In over 35 years of studying the repair of damaged kidneys, Bonventre suggests that the field may be reaching an inflection point. “The Harvard Stem Cell Institute basically has allowed us to look at kidney disease in a different and, in many cases, quite definitive way,” said Bonventre. “We’re understanding the processes much better so that we can now focus on the cell biology related to the intrinsic capacity for the kidney to renew itself.”
Collaboration among HSCI researchers has been key to advancing this understanding by sharing expertise as well as findings from model organisms such as the mouse and the zebrafish. “Andy McMahon is a world class investigator who has made enormous contributions to the understanding of the way the kidney matures during development,” said Bonventre. “It has been very productive to apply this knowledge to understanding repair in the adult organ.” The team is also using knowledge of the kidney’s ability to renew itself to find out how to protect it from further damage. “We have found in mice that we can precondition the kidney to be protected against a subsequent injury simply by temporarily cutting off blood flow to parts of the organ and coming back one to two weeks later and finding that when we cut off blood supply again the kidney is not damaged,” said Bonventre. “We want to understand what causes the protection against the second injury. Is there a cell that goes into the kidney, or some other factor involved?” If these protective factors can be found, they could potentially be developed as drugs or treatments that prevent kidney damage in highrisk individuals.
Another use of kidney cells grown in the laboratory is in screens for the potential toxicity of drugs before they are introduced into animals or humans. There really is no good model for in vitro kidney toxicity screening today, because the cells tend to lose their differentiated state and become less “kidney-like” or less “epithelial-like” outside the body. Bonventre and colleagues are working on ways to control cell behavior and maintain their state to make better predictive screens. “We will be working with Lee Rubin’s group at the HSCI Therapeutic Screening Center to help us screen for molecules that will keep cells differentiated in culture. If we can do that, we can use them for toxicology and for more sophisticated kidney assist devices,” said Bonventre.
Taking that technology back inside the body, one might even use the differentiated cells to create artificial tubules and nephrons with the help of bioengineered materials - completing the regeneration that the kidney is unable to do on its own.
Patients might not have to wait too long to see the benefits of this research. Based on animal studies that suggested an indirect role for stem cells in kidney repair, clinical trials aimed at preventing or rolling back kidney damage in cardiac patients have already begun.