MIT researchers imagine a way to help blood cells regenerate after radiation therapy

Patients with blood cancers, such as leukemia and lymphoma, are often treated by irradiating their bone marrow to destroy diseased cells. After treatment, patients are vulnerable to infection and fatigue until new blood cells are reconstituted.

MIT researchers have developed a way to help blood cells regenerate faster. Their method involves stimulating a particular type of stem cells to secrete growth factors that help precursor cells to differentiate into mature blood cells.

Using a technique called mechano-reduction, researchers developed mesenchymal stem cells (MSCs) on a surface whose mechanical properties are very similar to those of the bone marrow. This induced the cells to produce special factors allowing the differentiation of hematopoietic stem and progenitor cells (HSPC) into red and white blood cells, as well as into platelets and other blood cells.

"You can think of it as if you were trying to grow a plant," says Krystyn Van Vliet, Professor of Materials Science and Engineering Michael and Sonja Koerner, Professor of Biological Engineering and Assistant Vice President. "MSCs arrive and improve the soil so that progenitor cells can begin to proliferate and differentiate into the blood cell lines that you need to survive."

In a study on mice, the researchers showed that specially developed MSCs helped animals recover much more quickly from bone marrow irradiation.

Van Vliet is the main author of the study, which appears in the October 24 issue of the journal Stem cell research and therapy. The lead author of the paper is Frances Liu, a PhD winner at MIT. Kimberley Tam, postdoctoral fellow at the Singapore-MIT Alliance for Research and Technology (SMART), the recent MIT Ph.D. recipient, Novalia Pishesha, and former postdoc of SMART Zhiyong Poon, today At Singapore General Hospital.

Cellular drug factories

MSCs are produced throughout the body and can differentiate into a variety of tissues, including bone, cartilage, muscle and adipose tissue. They can also secrete proteins that help other types of stem cells differentiate into mature cells.

"They act like drug factories," says Van Vliet. "They can become cells of tissue lines, but they also pump many factors that alter the environment in which hematopoietic stem cells operate."

When cancer patients receive a stem cell transplant, they usually receive only HPSCs, which can become blood cells. Van Vliet's team showed previously that when mice also receive an MSC, they recover faster. However, in a given population of CSM, only about 20% produce the factors necessary to stimulate blood cell growth and bone marrow recovery.

"Left to themselves in the most modern cultural environments, MSCs become heterogeneous and they all express a variety of factors," Van Vliet said.

In an earlier study, Van Vliet and her colleagues at SMART showed that she could sort MSCs with a special microfluidic device that could identify the 20% promoting blood cell growth. However, she and her students wanted to improve this by finding a way to stimulate an entire population of CSMs to produce the necessary factors.

To do this, they had to first determine which factors were the most important. They showed that while many factors contribute to the differentiation of blood cells, the secretion of a protein called osteopontin was most strongly correlated with better survival rates in mice treated with MSCs.

The researchers then explored the idea of ​​"mechanoprimer" the cells so that they produce more necessary factors. Over the past decade, Van Vliet and other researchers have shown that altering the mechanical properties of surfaces on which stem cells are cultured can affect their differentiation into mature cell types. However, in this study, it has shown for the first time that mechanical properties can also affect factors that stem cells secrete before engaging in a specific tissue cell line.

Usually stem cells extracted from the body are grown on a glbad or rigid plastic plate. The MIT team decided to try to grow the cells on a polymer called PDMS and to vary its mechanical properties to see how this would affect the cells. They designed materials whose rigidity and viscosity varied, giving an idea of ​​how quickly the material stretches when stresses are applied.

The researchers found that MSCs grown on materials with very similar bone marrow mechanical properties produced as many factors as needed to cause HPSPCs to differentiate into mature blood cells.

Better recovery

The researchers then tested their specially developed MSCs by implanting them in mice whose bone marrow had been irradiated. Even though they did not implant with CPSH, this treatment rapidly repopulated animal blood cells and helped them recover faster than mice treated with MSCs grown on traditional glbad surfaces. They also recovered more rapidly than mice treated with the factor producing MSCs selected by the microfluidic sorting device.

"Studies on mice were models of radiotherapy commonly used to kill cancer cells in the clinic, but these therapies are extremely destructive and also destroy healthy cells," Liu said. "Our mechanized MSCs can help better support and regenerate healthy bone marrow cells faster in these mouse models, and we hope the same results will translate to humans."

The Van Vliet laboratory is currently conducting more animal studies in the hope of developing a combined treatment of MSC and HSPC that can be tested on humans.

"You can not survive very long with low numbers of blood cells," she says. "If you can reach your total number of whole blood cells more quickly at a normal level, your prognosis will be much better for the speed of your recovery."

The researchers also hope to study whether mechanopriming can lead to MSCs producing different factors that may stimulate the development of additional cell types that may be useful for treating other diseases.

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