Good things come in small packages, and therapeutic stem cells are no exception. They appear to be more effective if they are delivered individually wrapped, encapsulated in so-called microgels, rather than deposited in bulk. The main advantage of singly encapsulated stem cells is that they stay fresher, longer. That is, they are protected from immune attack and cleared more slowly from the body. Consequently, they promise to improve cell-based therapies, which often fail due to rejection by the patient’s immune system or graft-versus-host disease.

The microgel encapsulation of transplanted stem cells was described in a paper (“Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation”) that appeared July 16 in the Proceedings of the National Academy of Sciences (PNAS). According to this paper, which comes from the Wyss Institute at Harvard University, the delivery technique improved the performance of mesenchymal stem cells (MSCs) injected into mice.

“MSC therapies demonstrate particular promise in ameliorating diseases of immune dysregulation but are hampered by short in vivo cell persistence and inconsistencies in phenotype,” the article’s authors wrote. “Here, we demonstrate that biomaterial encapsulation into alginate using a microfluidic device could substantially increase in vivo MSC persistence after intravenous injection.” Specifically, in the mice, the approach improved the success of bone marrow transplants.

As far as the Wyss Institute team is aware, the article provides the first example of single-cell encapsulation being used to improve cell therapies. In addition, as noted by Angelo Mao, PhD, the article’s first author and a postdoc in the Wyss Institute laboratory of James Collins, PhD, the “encapsulated cells can be frozen and thawed with minimal impact on the cells’ performance, which is critical in the context of hospitals and other treatment centers.”

The advance described in the current paper builds on a method the Wyss Institute team previously developed. The method uses a microfluidic device to coat individual living cells with a thin layer of an alginate-based hydrogel, creating microgels. The process encapsulates cells with 90% efficiency, and the resulting microgels are small enough that they can be delivered intravenously, unlike the bulky hydrogels created by other methods.

When injected into mice, MSCs encapsulated using this technique remained in the animals’ lungs 10 times longer than “bare” MSCs, and remained viable for up to three days.

Because a large amount of MSCs’ clinical appeal lies in their secretion of compounds that modulate the body’s immune system, the researchers needed to test how microgel encapsulation affects MSCs’ ability to function and resist immune attack. Pursuing this thought, the researchers determined that “a combination of cell cluster formation and subsequent cross-linking with polylysine led to an increase in injected MSC half-life.”

Cross-linking stiffened the microgel stiffer and improved its resistance to the body’s immune system and clearance mechanisms; culturing the MSCs after encapsulation encouraged them to divide and produce more cells. When the new microgels were injected into mice, their persistence increased fivefold over the previous microgel design and an order of magnitude over bare MSCs.

To induce an immune response against the MSCs, the team incubated encapsulated cells in a medium containing fetal bovine serum, which is recognized by the body as foreign, before introducing them into mice. While the clearance rate of the encapsulated MSCs was higher than that observed without immune activation, it was still five times lower than that of bare MSCs. The microgels also outperformed bare MSCs when injected into mice that had a preexisting immune memory response against MSCs, which mimics human patients who are given multiple infusions of stem cells.

MSCs exposed to inflammatory cytokines respond by increasing their expression of immune-modulating genes and proteins, so the researchers next tested whether encapsulation in their new microgels impacted this response. They found that bare and encapsulated MSCs had comparable levels of gene expression when exposed to the same cytokines, demonstrating that the microgels did not impair MSC performance.

For their pièce de résistance, the team injected their MSC-containing microgels into mice along with transplanted bone marrow, half of which was immune-compatible with the recipient mouse and half of which was allogeneic, or an immune mismatch. Mice that received encapsulated MSCs had more than double the fraction of allogeneic bone marrow cells in their marrow and blood after nine days compared with mice that did not receive MSCs. Encapsulated MSCs also led to a greater degree of engraftment of the allogeneic cells into the host bone marrow compared to bare MSCs.

“One of the strong points of this work is that it uses a completely nongenetic approach to dramatically increase cell survival in transplant contexts, where it’s sorely needed,” said David J. Mooney, PhD, a Wyss core faculty member and lead of the Wyss Immuno-Materials Platform. “This technology nicely complements genetic engineering approaches, and in fact could be more efficient than attempting to directly modify immune cells themselves.”

The Wyss Institute’s microgel encapsulation technology could address various drug and cell delivery problems. Already, as noted in the PNAS article, the technology has the potential to sustain MSC survival and increase overall immunomodulatory capacity. It may improve MSC therapies in general.

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