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New research demonstrates bone-marrow derived stem cells can reverse genetic kidney disease

26.04.2006
Animal study shows promise for treatment of Alport syndrome

The discovery that bone-marrow derived stem cells can regenerate damaged renal cells in an animal model of Alport syndrome provides a potential new strategy for managing this inherited kidney disease and offers the first example of how stem cells may be useful in repairing basement membrane matrix defects and restoring organ function.

Led by researchers at Beth Israel Deaconess Medical Center (BIDMC), the findings are described in the Proceedings of the National Academy of Sciences (PNAS), which appears on-line the week of April 24, 2006.

Symptoms of Alport syndrome, the second most common genetic cause of kidney failure, usually appear in children, affecting the kidneys’ filtration system and typically leading to end-stage renal disease in the patient’s teens, 20s or 30s. The disease additionally causes deafness in some patients.

"This is one of 31 human diseases that occur because of genetic defects in the body’s extracellular matrix and basement membrane proteins, " explains the study’s senior author Raghu Kalluri, PhD, chief of the division of matrix biology at BIDMC and associate professor of medicine at Harvard Medical School.

Present throughout the body, the extracellular matrix (ECM) is made of collagens, proteogylcans, noncollagenous glycoproteins and in some tissues, elastin fibers. The ECM serves a unique role by constructing a "scaffold" for cells, thereby maintaining the structural integrity of many tissues.

"In normal kidneys, a specialized form of extracellular matrix known as the glomerular basement membrane [GBM], composed primarily of type IV collagen, is the key component of the blood filtration apparatus," says Kalluri.

However, in patients with Alport syndrome, mutations in three different type IV collagen genes cause structural damage to the GBM, leading to a breakdown of the organ’s filtration system, and resulting in the seepage of blood and protein into the urine and eventual kidney failure.

"With no known cure, treatment options for Alport syndrome are limited to kidney transplantation or lifelong dialysis," he adds. "Our lab set out to determine if bone marrow-derived stem cell therapy might provide another treatment option."

Using a mouse model of the disease, in which COL4A3 – one of the three type IV collagen genes that is mutated in Alport patients -- had been removed, the researchers transplanted allogenic bone marrow into the knockout mouse.

According to Kalluri, within a period of about four weeks, the investigators found that approximately 10 percent of the transplanted cells had incorporated into the damaged regions of the kidney glomeruli in the knockout mouse, emerging as healthy renal cells (podocytes and mesangial cells). This led to clear improvement in the animal’s kidney function and repair of the glomerular architecture defects.

"These results offer a possible therapeutic opportunity for both children and adults with Alport syndrome," he says. In addition, the new findings demonstrate that bone-marrow-derived stem cells can be used to repair extracellular/basement membrane defects, and according to Kalluri, the researchers’ next step will be to see if the use of embryonic stem cells and circulating adult stem cells will achieve the same function.

"This new evidence offers hope that this is a treatment strategy that can be explored for other diseases that result from extracellular matrix defects," he notes.

Study coauthors include BIDMC researchers Hikaru Sugimoto, MD, PhD, Thomas Mundel, MD, PhD, Malin Sund, MD, PhD, and Liang Xie, PhD, and Dominic Cosgrove of Boystown National Research Hospital, Omaha, Nebraska.

Bonnie Prescott | EurekAlert!
Further information:
http://www.bidmc.harvard.edu

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