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Method Boosts Differentiation Of Stem Cells Into Blood Cells After Radiation.

CAMBRIDGE, Mass., October 24, 2018 -Patients with blood cancers such as leukemia and lymphoma are often treated by irradiating their bone marrow to destroy the diseased cells.

But after the treatment, patients are vulnerable to infection and fatigue until new blood cells grow back.

Now, MIT researchers have now devised a way to help blood cells regenerate faster by stimulating a particular type of stem cell to secrete growth factors that help precursor cells differentiate into mature blood cells.

Using a technique known as mechano-priming, the researchers grew mesenchymal stem cells (MSCs) on a surface whose mechanical properties are very similar to that of bone marrow.

This induced the cells to produce special factors that help hematopoietic stem and progenitor cells (HSPCs) differentiate into red and white blood cells, as well as platelets and other blood cells.

"You can think about it like you're trying to grow a plant," said Krystyn Van Vliet, a professor of biological engineering. "The MSCs are coming in and improving the soil so that the progenitor cells can start proliferating and differentiating into the blood cell line-ages that you need to survive."

In a mouse study, the researchers showed that the specially-grown MSCs helped the animals to recover much more quickly from bone marrow irradiation.

MSCs are produced throughout the body and can differentiate into a variety of tissues, including bone, cartilage, muscle, and fat.

They can also secrete proteins that help other types of stem cells differentiate into mature cells.

"They act like drug factories," Van Vliet said. "They can become tissue lineage cells, but they also pump out a lot of factors that change the environment that the hematopoietic stem cells are operating in."

When cancer patients receive a stem cell transplant, they usually receive only HPSCs, which can become blood cells. The team has shown previously that when mice are also given MSCs, they recover faster.

However, in a given population of MSCs, usually only about 20 percent produce the factors that are needed to stimulate blood cell growth and bone marrow recovery.

Left to their own devices in the current state-of -the-art culture environments, MSCs become heterogeneous and they all express a variety of factors.

In an earlier study, the researchers showed that MSCs can be sorted with a special microfluidic device that can identify the 20 percent that promote blood cell growth.

However, they wanted to improve on that by finding a way to stimulate an entire population of MSCs to produce the necessary factors.

To do that, they first had to discover which factors were the most important.

While many factors contribute to blood cell differentiation, secretion of a protein called osteopontin was most highly correlated with better survival rates in mice treated with MSCs.

They then explored "mechano-priming" the cells to produce more of the necessary factors.

Over the past decade, researchers have shown that varying the mechanical properties of surfaces on which stem cells are grown can affect their differentiation into mature cell types.

However, in this study, for the first time, they showed that mechanical properties can also affect the factors that stem cells secrete before committing to a specific tissue cell lineage.

Usually, stem cells removed from the body are grown on a flat sheet of glass or stiff plastic. The team decided to try growing the cells on a polymer called PDMS and to vary its mechanical properties to see how that would affect the cells.

They designed materials that varied in both their stiffness and their viscosity, which is a measure of how quickly the material stretches under stress.

MSCs grown on materials with mechanical properties most similar to bone marrow produced the greatest number of the factors necessary to induce HPSPCs to differentiate into mature blood cells.

The researchers tested their specially-grown MSCs by implanting them into mice that had had their bone marrow irradiated.

Even though they did not implant any HSPCs, this treatment quickly repopulated the animals' blood cells and helped them to recover more quickly than mice treated with MSCs grown on glass surfaces.

They also recovered faster than mice treated with the factor-producing MSCs that were selected by the microfluidic sorting device.

The lab is now performing more animal studies in hopes of developing a combination treatment of MSCs and HSPCs that could be tested in humans.

They also hope to study whether mechanopriming can induce MSCs to produce different factors to stimulate the development of additional cell types that could be useful for treating other diseases.

"You could imagine that by changing their culture environment, including their mechanical environment, MSCs could be used for administration to target several other diseases," such as Parkinson's disease, rheumatoid arthritis, and others, Van Vliet said.

Citation: Frances D. Liu et al., Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome. Stem Cell Research & Therapy, 2018 9:268, 24 October 2018


Contact: Krystyn J. Van Vliet,
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Title Annotation:Advanced Stem Cell Technology
Publication:Stem Cell Lab World
Date:Nov 12, 2018
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