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Helping transplanted stem cells stay and do their jobs



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Hematopoietic stem cell transplants in the bone marrow have become standard treatment for many conditions, including blood and lymphatic system cancers, sickle cell disease, inherited metabolic disorders, and radiation damage. Unfortunately, many bone marrow transplants fail because of rejection of the patient's immune system or graft-versus-host disease (in which grafted marrow cells attack the patient's healthy cells), which can be fatal. Mesenchymal stromal cells (MSCs) are known to secrete compounds that modulate the immune system and have shown promise for mitigating these problems in animal experiments. However, the clinical results obtained with MSCs have been disappointing so far, as they are rapidly removed from the body and can be attacked by the immune system of patients, and efforts to encapsulate MSCs in protective biomaterials have resulted the creation of large, bulky hydrogels that can not be administered intravenously and compromise cell functions.

Today, as part of a first-ever scientific, researchers from the Wyss Institute for Biologically Inspired Engineering, the Harvard SEAS (John A. Paulson School of Engineering and Applied Sciences). and the Harvard Stem Cell Initiative (HSCI) exhibit a unicellular encapsulation technology that protects grafted MSCs from clearance and immune attack and improves the success of bone marrow transplants in mice. The work is published in PNAS.

"To our knowledge, this is the first example of the use of unicellular encapsulation to enhance cell therapies, which are increasingly prevalent for the treatment of many diseases," said the first author Angelo Mao, Ph.D., former graduate student in the laboratory of the Wyss Core faculty member and head of the Wyss Immuno-Materials platform David Mooney, Ph.D. who is now a postdoctoral fellow with James Collins, Ph.D., faculty member of Wyss Core. "And our encapsulated cells can be frozen and thawed with minimal impact on cell performance, which is essential in the context of hospitals and other treatment centers."

This breakthrough is based on a method previously developed by the team, which uses a microfluidic device to coat individual living cells with a thin layer of alginate-based hydrogel, creating what they call "microgels". . The process encapsulates the cells with 90% efficiency and the microgels obtained are small enough to be administered intravenously, unlike the bulky hydrogels created by other methods. When injected into mice, encapsulated MSCs using this technique remain in animal lungs ten times longer than "bare" MSCs and remain viable for up to three days.

Because much of the clinical benefit of MSCs lies in the secretion of compounds that modulate the body's immune system, researchers have had to test how microgel encapsulation affects the ability of MSCs to function and resist immune attacks. They modified their original alginate microgel by adding another compound that binds to alginate and makes the microgel more rigid and better able to resist the immune system and the clearance mechanisms of l & # 39; body. They also cultured MSCs after encapsulation to encourage them to divide and produce more cells. When these new microgels were injected into mice, their persistence was multiplied by five compared to the previous design of the microgel and by an order of magnitude compared to bare MSCs.

To induce an immune response against MSCs, the team incubated encapsulated cells in medium containing fetal calf serum, recognized by the body as foreign, before introducing them into the mouse. While the clearance rate of encapsulated MSCs was higher than that observed without immune activation, it was still five times lower than that of nude MSCs. The microgels also outperformed the naked MSCs when injected into mice with a pre-existing immune response against MSC memory, mimicking human patients who receive multiple stem cell infusions.

MSCs exposed to inflammatory cytokines respond by increasing their expression of immunomodulatory genes and proteins. The researchers then checked whether encapsulation in their new microgels had affected this response. They found that naked and encapsulated MSCs had comparable levels of gene expression when exposed to the same cytokines, thus demonstrating that microgels did not alter MSC performance.

For its part, the team injected its microgels containing MSCs to mice, as well as transplanted bone marrow, half of which was compatible with the recipient mouse and the other half allogeneic or immune imbalance. Mice that received encapsulated MSCs had more than double the bone marrow allogeneic cell fraction in the marrow and blood after nine days compared to mice that did not receive MSC. Encapsulated MSCs also led to a higher degree of allogeneic cell transplantation in the host bone marrow compared to bare MSCs.

"One of the strengths of this work is that it uses a totally non-genetic approach to dramatically increase cell survival in transplant settings, where it is absolutely necessary," said Mooney, also a professor of Bioengineering of the Robert P. Pinkas family in Mers "This technology perfectly complements genetic engineering approaches and might actually be more effective than trying to directly alter the immune cells themselves."

The Wyss Institute Validation Project Program supports the advancement of this approach as a possible treatment for ischemia (narrowing of blood vessels) in human patients and hopes to demonstrate clinical viability in the near future. Validation projects are technologies with potential high-impact applications that have progressed successfully through significant concept refinement and meet predefined criteria for technology, product development and intellectual property.

"This technology simultaneously solves multiple issues related to bone marrow transplants and stem cell therapies using an elegant, biomaterial-based approach, which represents the kind of interdisciplinary thinking we value so much at the Wyss Institute," he said. said Donald Ingber, founding director of Wyss, MD, Ph.D., is also a Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at the Boston Children's Hospital, as well as a professor of bioengineering at SEAS. "We are delighted to support this project as it moves towards clinical validation, and we look forward to seeing other potential applications of microencapsulation to address drug and drug delivery issues." cells. "


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More information:
Angelo S. Mao el al., "Programmable microencapsulation to improve the persistence of mesenchymal stem cells and immunomodulation," PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1819415116

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Helping transplanted stem cells stay and do their work (July 15, 2019)
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