Some Cell Therapies Work by Dying, New Research Shows

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Certain cell therapies that hold promise for treating autoimmune diseases like multiple sclerosis might work not because of the way the cells live in the body during treatment, but because of how they die.

A better understanding of how these cell therapies work “is important in designing treatment protocols that improve disease outcomes,” Tracy Heng, PhD, a professor at Monash University, in Australia, said in a press release announcing the findings of a new study that uncovered some of the workings of mesenchymal stromal cells, or MSCs, also sometimes called mesenchymal stem cells.

Heng, also deputy head of the immunity program at the Biomedicine Discovery Institute at Monash, and her colleagues reported their findings in a study titled “Mesenchymal stromal cell apoptosis is required for their therapeutic function,” published in Nature Communications.

MSCs are a specific type of stem cell that is able to grow and differentiate into bone, cartilage, muscle, and fat cells, as well as connective tissue. When these cells are given therapeutically, they are known to exert anti-inflammatory effects.

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It has long been assumed that MSCs exhibit their inflammation-reducing effects by living in the body and secreting anti-inflammatory signaling molecules. However, “there is little evidence that these cells even survive infusion or injection,” the researchers wrote.

Through a series of detailed cell-tracking experiments, the scientists at Monash now demonstrated that, when MSCs are administered to the lungs of mice with asthma, they promptly die and are cleared within a day. More specifically, administered MSCs undergo a type of cell death called apoptosis.

When people think of a cell dying, they might think of the cell being physically ripped apart or bursting, with its contents spewing out, perhaps after an injury. This does happen, and it’s called necrosis. Importantly, this form of cell death usually means that something is seriously wrong, so it triggers the immune system to activate.

By contrast, apoptosis is a form of programmed cell death, which happens as a part of many normal bodily processes. When cells undergo apoptosis, they basically break themselves down into neat little fragments of cellular debris, which can then be cleared away by immune cells. Notably, apoptosis is “immunologically silent,” meaning that cellular debris from cells that die via apoptosis doesn’t activate the immune system. As an example, apoptosis occurs early in pregnancy to eliminate unwanted cells, such as those between the fingers of a baby’s developing hand.

In the asthma model, treatment with MSCs that had already been injured to the point that they would soon undergo apoptosis was similarly as effective at reducing inflammation as treatment with living cells.

“Apoptotic MSCs exerted immunosuppressive [anti-inflammatory] effects in the lungs and inhibited allergic asthma to a similar extent as administration with viable MSCs,” the scientists wrote.

In other experiments, the researchers engineered MSCs that lacked certain genes critical for apoptosis, so that the cells couldn’t undergo this type of programmed cell death. These “apoptosis-resistant” MSCs were markedly less effective at suppressing the immune response in the asthma model.

Similar results also were found in mice with experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis.

“These findings indicate that apoptosis of MSCs is necessary for efficient in vivo [in the body] immunosuppression and therapeutic efficacy,” the team wrote.

Further experiments unraveled the general mechanism behind this effect: when the MSCs are injected into mice and undergo apoptosis, the fragments of these cells are taken up by immune cells like macrophages through a specific form of phagocytosis or cellular eating called efferocytosis.

Unlike the more usual form of cellular eating, called phagocytosis, efferocytosis also is immunologically silent, and does not cause the activation of other branches of the immune system. In fact, after the macrophages take MSC fragments, their activity became markedly more anti-inflammatory.

“Taken together, our data demonstrate that efferocytosis of apoptotic MSCs causes sustained alterations in [macrophage] immunometabolism and function that directly inhibit lung inflammation,” the researchers wrote.

According to the researchers, the new findings have “broad implications for the effective translation of cell-based therapies.” MSCs currently are being investigated in clinical trials as therapeutic agents, the team noted.

“Our data suggest that the inhibitory effects of MSC administration are mediated by the host phagocytic response to MSC apoptosis, rather than cell-intrinsic immunosuppression by viable MSCs,” the team concluded.

“By better understanding how immune cells respond to dying MSCs, we may be able to develop new therapeutic strategies that directly target the responding immune cell population to bring about anti-inflammatory effects,” Heng said.

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