Mesenchymal stem cells treat diabetic angiopathy

Scientists from the University of Illinois at Urbana-Champaign, USA, have found that muscle-tissue stem cells can improve blood flow in patients with diabetes who develop peripheral artery disease (PAD). A new study, published in Theranostics, found that injection of the stem cells stimulates the growth of new blood vessels, improving blood flow in the affected tissues and functioning of the limbs.

Scientists from the University of Illinois have shown in mice that in addition to promoting the growth of blood vessels, transplanted stem cells also induced changes in gene expression in surrounding tissues, which stimulated the release of factors that reduce inflammation and improve blood circulation.

“PAD is very common in diabetic patients, but it is difficult to diagnose because patients experience symptoms when the disease is already at an advanced state,” – said study leader Wawrzyniec Lawrence Dobrucki, a professor of bioengineering and of medicine.

“When the PAD is left untreated, it often leads to foot ulcerations and limb amputations – thousands every year in the United States. It’s a serious, costly and debilitating disease.”

In PAD, the arteries in the limbs become narrowed (diabetic angiopathy), causing pain and limiting mobility due to lack of blood and oxygen. There are few options for treating PAD. Some medications are aimed at increasing perfusion in the limbs, but they are not effective enough, Dobrucki said.

Clinicians recommend exercise, but for patients with PAD, they can be painful and difficult to perform. In addition, physical activity may be unacceptable in other cardiovascular complications. Many patients require surgery to place vascular stents or an arterial bypass.

The Dobrucki group partnered with Marni Boppart, professor of kinesiology and community health, to study the effect of stem cell injection on arterial narrowing sites. Boppart is an expert on mesenchymal stem cells (MSCs), which play an important role in healing injuries and regenerating muscles and other tissues.

One of their studies was aimed at studying various individual growth factors promoting the formation of blood vessels (a process called angiogenesis), but none of them brought the expected result.

“Angiogenesis is a sophisticated process involving many growth factors and interactions between key proteins,” – Dobrucki said. “That’s why we used a more nature-inspired therapy to promote angiogenesis in PAD-affected limbs and used the stem cells. They know what to release, how much and when to stop, for example. They also respond to and modify the tissue microenvironment to optimize their therapeutic effect.”

Researchers surgically narrowed the femoral artery in one leg of diabetic mice. They then injected MSCs, obtained from the muscles of young mice, into the legs of the experimental animals, while the control group received injections of saline.

Then they used non-invasive imaging techniques developed in Dobrucki laboratory to monitor blood flow and formation of blood vessels formation in the mice, comparing the experimental and control groupsand the affected and nonaffected legs in each mouse.

“We clearly demonstrated the capacity for MSCs to increase angiogenesis, peripheral perfusion and muscle function,” – Boppart said. “We saw that MSCs promoted muscle healing by creating new vessels in the tissue that compensated for restricted blood flow. MSC transplantation provides the opportunity to maximize vessel growth in PAD to maintain or rejuvenate skeletal muscle.”

The researchers also analyzed gene expression within the tissue and found that in mice given the stem cell injections, the gene expression in the leg with PAD was close to that of the unaffected leg. Scientists also showed that in the experimental group of animals, unlike the control group, genes that participate in the fight against some diabetic complications were activated, for example, genes associated with inflammation were repressed.

“Our results suggest that stem cell treatment could be used for those patients at severe stages of PAD who cannot exercise,” – Dobrucki said. “Stem cell treatment could help bring them to the level where they can start exercising, or it could save an extremity before it needs amputation.”

In the future study, scientists hope to identify subpopulations of MSCs that will show the greatest potential for treating PAD, and to optimize the conditions for the isolation of these cells from adipose tissue and skeletal muscles. In addition, the researchers want to find out how long MSCs remain active after the injection.

“We also are attempting to develop an acellular approach to rejuvenation of muscle repair and growth,” – Boppart said. “We hope to identify the optimal composition of factors that the cells release, as well as the medium for release.”