Cross-section view of injectable sponge
An electron microscopy image of an injectable sponge, developed by HSCRB researchers to enhance T-cell regeneration after a bone marrow transplant. Credit: Harvard University.

Bone marrow transplants, also known as blood stem cell transplants, are life-saving treatments for aggressive diseases such as leukemia and infections such as HIV. The procedure entails infusing blood stem cells from a matched donor into the patient to ‘reset’ the blood and immune system. The healthy stem cells develop into many different cell types in the patient, including immune cells.

To prevent the patient’s body from rejecting the transplanted cells, patients undergo chemotherapy and radiation to suppress their own immune cell production. This intensive treatment compromises the functioning of normal cells in the bone marrow, including their ability to generate T-cells. The result is profound, long-term, post-transplant immune deficiency. It puts patients at risk for infectious diseases and complications such as graft-versus-host-disease.

Now, bioengineers and stem cell biologists at Harvard have developed an injectable, sponge-like gel that enhances the production T-cells after a bone marrow transplant. This bioengineered device can be injected under the skin at the time of the transplant. It helps revive the immune system after bone marrow transplantation by increasing the quantity and diversity of immune cells,

The research is published in Nature Biotechnology.

The problem

“T-cell deficiency and dysfunction is a life-threatening challenge, especially in transplant settings,” said David Scadden, the Gerald and Darlene Jordan Professor of Medicine, professor of stem cell and regenerative biology, co-director of the Harvard Stem Cell Institute (HSCI), and co-senior author on the paper. “Our research demonstrates a simple-to-administer, off-the-shelf solution that can enhance T-cell regeneration after stem cell transplantation.”

“We have shown that the idea of creating cell factories in the body can be used in the context of stem cells for regenerative medicine,” said David Mooney, the Robert P. Pinkas Family Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), HSCI affiliate faculty member, and co-senior author on the paper.

Previous research into reinvigorating the immune system after a bone marrow transplant focused on improving the function of the thymus, the organ that is necessary for T-cell production. Mooney, Scadden and their team focused on the bone marrow, which is the home of the 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.

What the researchers did

Drawing upon the Mooney Lab’s pioneering research in the development of biomaterials for providing cell-instructive cues, 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.
Cross-section of sponge
Three weeks after the device is injected, the outside is covered with a bone shell and the inside of the sponge resembles vascularized bone marrow. Credit: Harvard University.

What they found

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

“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 faculty member 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.”

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 steps

The researchers plan to scale up their research to be applicable in a clinical setting.

“The ultimate goal is to make this into a product that physicians can prescribe and use,” said Scadden.

To that end, this project received funding and strategic support from Harvard’s Blavatnik Biomedical Accelerator, which advances early-stage biomedical research toward key milestones that would validate the innovations in the eyes of prospective corporate partners or investors. Harvard’s Office of Technology Development is exploring a number of avenues for further development and commercialization of the technology. 

In this article

Photo of David Scadden

David Scadden, M.D.

Professor of Stem Cell and Regenerative Biology

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

The original version of this story can be found on the SEAS website.

Source publication: Shah, N. J. et al. (2019). An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation. Nature Biotechnology. DOI: 10.1038/s41587-019-0017-2