UCSD Jacobs School of Engineering

A bioengineered factory for T-cells

Injectable sponge-like gel enhances the quantity and quality of T-cells

A histological section of bone (solid blue-green) containing blood stem cells (red dots) generated using a biomaterial (red strands). Image courtesy of Nisarg Shah

San Diego, Calif., Feb. 11, 2019 -- Bone marrow transplants, also known as hematopoietic stem cell transplants, are life-saving treatments for aggressive diseases, such as leukemia and multiple myeloma, and infections such as HIV. The procedure entails infusion of blood stem cells from a matched donor into the patient to "reset" the blood and immune system.

Immune cells develop from blood stem cells that reside in the bone marrow. In order to treat the disease and prevent the patient's body from rejecting the transplanted cells, patients undergo intensive conditioning, which involves administration of chemotherapy and radiation. However, the conditioning regimen also significantly compromises the functioning of normal cells in the bone marrow, and therefore compromises their ability to regenerate the immune system. This includes a reduced ability to generate T-cells, and causes profound long-term post-transplant immune deficiency, increases the risk of opportunistic infectious diseases and immunological complications such as graft-versus-host-disease.

Now, engineers and stem cell biologists have developed an injectable sponge-like gel that enhances the production of T-cells after a bone marrow transplant, increasing the quantity and diversity of these key components of the immune system. This bioengineered device can be injected under the skin at the same time of the transplant to help revive the immune system after bone marrow transplantation.

The research is published in Nature Biotechnology.

“T-cell deficiency and dysfunction is a life-threatening challenge, especially in transplant settings,” said co-senior author David Scadden, a professor of medicine at Harvard University and co-director of the Harvard Stem Cell Institute. “Our research demonstrates a simple to administer, off-the-shelf solution that can enhance T-cell regeneration after stem cell transplantation.”

“We also found that not only are we enhancing the rate at which these T-cells form after transplant but we are also increasing the diversity in the types of T-cells that are formed,” said Nisarg Shah, a former postdoctoral fellow and the lead author on the paper, who is now a professor in the Department of NanoEngineering at the University of California San Diego. “So, we are improving not only the number of T-cells but also, potentially, the breadth of pathogen recognition capabilities and protection.”

Previous research into reinvigorating the immune system after a bone marrow transplant has focused primarily on improving the function of the thymus, the organ that is necessary for T-cell production. The team focused on the bone marrow, which is the home of blood stem cells, and devised a method to expand the cells that migrate to the thymus to eventually give rise to new T-cells. These cells, known as common lymphoid progenitors, are made in the bone marrow.

“Our goal was to enhance the production of these cells, which are like the entry product to the foundry that produces T-cells, by creating a little bone marrow-like environment,” said Scadden.

The researchers engineered a sponge-like cell factory, with large pores that allows cells to move in and out. The sponge has two built-in proteins, one that recruits outside cells and the other to create the T-cell progenitors. The first, called bone morphogenetic protein 2, recruits local cells and encourages them to become bone cells. Once the sponge resembles vascularized bone marrow, the second protein encourages the blood stem cells living in the device to produce T-cell progenitors. 

When the researchers tested the device in mice receiving a hematopoietic stem cell transplant, they found that the mice treated with the scaffold generated T-cells faster when compared with mice that did not.

The researchers also found that in mice with the implanted scaffold, the frequency of graft versus host disease, in which donor cells may attack the patient’s healthy tissues and organs, was significantly reduced.

Next, the researchers aim to scale up the research to be applicable in a clinical setting.

Immuno-engineering

Nisarg Shah is a faculty member of a new agile research center at the UC San Diego Jacobs School of Engineering that will develop and leverage nano-scale tools to engineer the immune system for a wide range of preventive and therapeutic applications. More details on this new center to come.

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Paper title: “An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation.” Co-authors include Angelo S. Mao, Ting-Yu Shih, Matthew D. Kerr, Azeem Sharda, Theresa Raimondo, James C. Weaver, Vladimir D. Vrbanac, Maud Deruaz, Andrew M. Tager, and David J. Mooney.

This research was supported by the National Institutes of Health, the Cancer Research Institute and the Blavatnik Biomedical Accelerator Program at Harvard University.  

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