Mesenchymal stromal cells (MSCs) can leave you guessing. For example, MSCs might be sufficiently potent to count as stem cells—or not. In the latter case, they may count as progenitor cells. Another area of uncertainty is of more than semantic import. Although MSCs are known to modulate inflammation, it is unclear why MSCs have performed inconsistently in clinical applications against inflammatory diseases such as allergies, arthritis, cancers, and COVID-19.

There is a mystery within the mystery, said scientists at Duke University. The team, led by Anthony Filiano, PhD, assistant professor in neurosurgery, reported that solving the outer mystery, the inconsistent anti-inflammatory performance of MSCs, may depend on solving an inner mystery—the peculiar ability of MSCs to suppress inflammation long after they have been cleared from the body.

“While MSCs are widely used in clinical trials due to their ability to modulate inflammation, their success over the past 25 years has been varied—something that is likely a result of us not being able to totally understand how they work,” said Filiano. “What we do know, is that after MSCs are injected into the body, they travel to the lungs and other tissues and then are rapidly cleared.

“Despite this, MSCs suppress the inflammatory response long-term. If the reasons for why and how this happens can be determined, the information could be very helpful in developing new treatments for a variety of inflammatory diseases.”

To study the lingering anti-inflammatory effect exerted by departed MSCs, Filiano and colleagues injected human cord tissue-derived MSCs (hCT-MSCs) into mice with induced lung inflammation. Twenty-four hours later, the mouse lungs underwent analysis.

The results appeared November 9 in an article published by the journal Stem Cells. According to the article’s first author, Hyunjung Min, PhD, the scientists saw that “pieces of the MSCs had been engulfed by monocytes and macrophages, in effect clearing them from the animals’ systems. We also noted long-term transcription changes in the cells that ate pieces of MSCs suppressed the activation of T cells.”

Next, using a combination of computational and pharmacological approaches, the researchers identified potential receptors on monocytes and macrophages that mediated their interactions with the hCT-MSCs and blocked interaction with a pharmacological inhibitor. They also identified a key cytoplasmic organelle in hCT-MSCs necessary to reprogram the monocytes and macrophages.

“Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p‐bodies), we generated p‐body-deficient hCT‐MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo,” the article’s authors detailed. “hCT‐MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p‐body deficient hCT‐MSCs were engulfed by infiltrating lung monocytes and macrophages, p‐body deficient hCT‐MSCs failed to suppress inflammation and downregulate MHC‐II.”

The scientists emphasized their essential findings in their article’s title: “Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies.”

MSCs are stem cells that can be isolated from bone marrow, adipose, and other tissue sources. Their ability to differentiate into a variety of cell types, along with their capability to self-renew, repair, and heal, make them attractive candidates for therapeutic use, provided their mechanisms are better understood.

“Our results shed light on how MSCs can modulate the inflammatory response without long-term engraftment using a previously undescribed form of cell communication,” said Filiano, “and explain how MSCs have extended beneficial effects on the body despite being cleared just hours after administration.”

“Overall,” the article’s authors concluded, “we identified a novel mechanism by which hCT‐MSCs indirectly suppressed a T‐cell response by directly interacting and reprogramming monocytes and macrophages via p‐bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long‐term effects to suppress inflammation.”

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