Program Leader: Joseph V. Bonventre, MD, PhD

The HSCI Kidney Program's central goal is to advance therapies for kidney disease by combining principles of stem cell and developmental biology with an understanding of injury and repair mechanisms. Nephrons, which are the key functional units of the kidney, consist of a filtering unit, 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 and the ability of the kidney to function is impaired. Consequently, the team has identified the tubule cells in the kidney nephron as its focus, with a special emphasis on the "proximal tubule cells," which comprise a large part of the nephron.

To watch a video of this program, click here.

Understanding Repair Mechanisms

Many theories exist on kidney repair. However, a recent study by HSCI Affiliated Faculty member Benjamin Humphreys, MD, PhD, HSCI Executive Committee member Andrew McMahon, PhD, and Joseph Bonventre, MD, PhD, head of the HSCI Kidney Disease Program, and their team went a long way toward elucidating how the tubules repair themselves. By tagging the mature epithelial cells that form the tubule walls with a fluorescent protein, the 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 from local tissue-specific stem cells in the tissue between the tubules. Cells that derive from the bone marrow and enter the kidney after injury might not be sitting on the sidelines, however. Other evidence suggests that they may be offering some assistance in stimulating the epithelial cells to multiply.

Multiple Skill Sets Applied to Multiple Animal Models

This past year, one of the most striking advances in the HSCI Kidney Program has been the solidification of interactions between investigators in traditionally separate specialties, including high-level cell and molecular biology of the kidney, pathophysiology of kidney disease, and developmental biology. The program's researchers have approached fundamental problems with a clinical perspective and both short-term and long-term goals of therapeutic applicability in patients.

Collaboration among HSCI researchers has led to sharing expertise and findings from different model organisms and technologies. In zebrafish, new advances have been made in identifying the various segments of the tubular structure. Because Polycystic Kidney Disease (PKD) is the most common genetic kidney disease and accounts for 10% of all people on dialysis, the team is in the process of creating a PKD-specific iPS cell line. Development of this and additional disease-specific cell lines will enable superior modeling of the disease in vitro, leading to a better understanding of disease and ultimately screens for the identification of new treatments.

In Vitro Kidney Cells

Another important use of kidney cells grown in the laboratory is to screen drugs for potential toxicity before they are introduced into animals or humans. There 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. Understanding how to drive an epithelial cell back toward the differentiated state it normally possesses inside the body will enable the development of more accurate preclinical toxicity testing systems. The group's strategy builds on the work of other HSCI researchers that have found that a cell's identity may be governed by only two or three master transcription factors. By "reprogramming" cells using these key proteins, a cell's identity can be changed fundamentally.

"We will also be working with Lee Rubin's group at the HSCI Therapeutic Screening Center to help us screen for molecules that modulate the differentiation state of cultured epithelial cells. If we can do that, we can use them for toxicology and for more sophisticated kidney assist devices," Bonventre said. Taking this 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.