Not all stem cell-based therapies act by replacing diseased or damaged cells. Many treatments in clinical development rely on the injected stem cells releasing proteins which trigger the slow down or even reversal of damage caused by disease or injury. A new CIRM-funded study that’s developing a stem cell therapy for a rare kidney disease uncovered a similar mechanism but with an intriguing twist. The research, published this week in Scientific Reports, suggests that the stem cells shed tiny vesicles that essentially act like sponges by trapping proteins thought to be responsible for damaging the kidney.

Amniotic fluid stem cells: a promising approach to treating kidney disease

Network of blood-filtering blood vessels in the kidney. Image: Wikipedia

In previous studies the research team, from the Saban Research Institute of Children’s Hospital Los Angeles (CHLA), had shown that amniotic fluid stem cells can help slow the progress of Alport syndrome when injected into the kidneys of mice engineered to mimic symptoms of the disease. Alport syndrome is a genetic disease that damages the kidney’s capillaries – tiny blood vessels – which help filter the body’s blood supply. This progressive damage causes blood and proteins to leak into the urine, and leads to high blood pressure and swelling in the legs and around the eyes.

Cells in the kidney release a protein called VEGF, a stimulator of new blood vessel growth, which plays an important role in maintaining just the right balance of capillaries within the blood-filtering structures of the kidney. Excessive levels of VEGF have been associated with many diseases including kidney disorders like Alport syndrome. Although the protective effects of amniotic fluid stem cells in the mouse model of Alport syndrome were not understood, the CHLA team suspected that the cells could be interfering with the effects of the extra VEGF.

Extracellular vesicles: just another trick that nature has up its sleeve
Specifically, the scientists examined whether so-called extracellular vesicles released from the stem cells are responsible for reducing VEGF activity and slowing the disease. These vesicles are tiny pieces of cell membrane that bud off from the stem cell and carry along proteins and other cell components. Scientists used to think the vesicles were just cellular discards but countless studies have established that they actually play an important role in communication between cells.

The team showed that the vesicles released by amniotic fluid stem cells contained receptors for VEGF. When those vesicles were added to a petri dish containing VEGF and kidney blood vessel cells, the vesicles reduced the VEGF activity and protected the cells from damage. But when vesicles from stem cells lacking the VEGF receptors were used, that protection was lost. First author Sargis Sedrakyan, PhD summed up the results in a press release:

“We have demonstrated that these vesicles can be used to regulate VEGF activity and prevent the [kidney] capillary damage. We can efficiently use the vesicles to help restore normal kidney function by curbing the progression of endothelial damage in the filtration unit of the kidney.”

Back in 2013, first author Sargis Sedrakyan summarized his research in this 30 second video for the CIRM Grantee Elevator Pitch Challenge. 

Vesicles from aminotic fluid stem cells beat out FDA-approved VEGF blocker
Now anti-VEGF antibody proteins that can tightly bind and inhibit VEGF are readily available and have even been approved by the Food and Drug Administration for other disorders. So why even bother with these vesicles as a possible therapeutic strategy for Alport syndrome? Well, in side-by-side comparisons, it turns out the stem cell-derived vesicles, but not the anti-VEGF antibodies, could not only trap the VEGF but also put the brakes on VEGF production. So, it seems that the vesicles have additional properties that could make them more ideal than current approaches.

And as indicated in the press release, the CHLA team is eager to continue exploring this therapeutic strategy:

“The team’s next step will be to validate the stem cell-derived vesicle in different types of kidney disease with the final aim of finding a therapy that is effective for all patients who suffer from chronic kidney disease.”