Some Cell Therapies Reduce Inflammation Precisely Because the Transplanted Cells Die

First generation stem cell therapies have been demonstrated to reduce chronic inflammation, but are unreliable when it comes to producing other benefits. Since very few transplanted cells survive, it was thought that benefits are produced via signaling that changes the behavior of native cells. This has led to work on therapies that deliver extracellular vesicles released by stem cells rather than the cells themselves. That such therapies produce benefits in similar ways to stem cell therapies in animal models suggests that signaling does play an important role.

In some cases, however, transplanted cells die rapidly, too rapidly for signaling to be a plausible mechanism for the resulting suppression of inflammation. Here, researchers provide evidence to show that the death and later clearance of the remains of these transplanted cells is the process by which inflammation is reduced. More research is needed to better understand how exactly this works, perhaps leading to a way to directly manipulate native cells to reproduce the changes in regulation of inflammation that result from the death of transplanted cells.

Mesenchymal stromal cell apoptosis is required for their therapeutic function

Multipotent mesenchymal stromal cells (MSCs) are a heterogeneous population of cells isolated from bone marrow and other tissue stroma that have immunosuppressive and anti-inflammatory properties. In many animal models of disease, MSCs have demonstrated therapeutic efficacy regardless of major histocompatibility complex or species barriers. It remains unclear how MSCs isolated from different tissues or species could exert therapeutic effects on such a wide range of unrelated diseases.

The current consensus is that therapeutic applications of MSCs are based on their secretion of a wide array of cytokines, chemokines, and subcellular particles5. However, MSCs do not engraft and there is little evidence that these cells even survive infusion or injection. Studies tracking MSCs after intravenous administration reported lung entrapment, upregulation of apoptosis-associated genes and presence of apoptotic bodies in the lungs. Only dead MSCs were detected in the lungs and liver 24 hours after administration. In a graft versus host disease study, it was demonstrated that only patients whose immune cells were able to induce apoptosis in MSCs responded to MSC therapy, suggesting that MSC apoptosis may contribute to clinical response.

In the current study, we generated apoptosis-refractory human MSCs to test whether inhibiting cell death in MSCs would abrogate their therapeutic efficacy, thereby establishing that apoptosis of MSCs is necessary for the immunomodulatory effects exerted by their infusion. Our data demonstrated that MSC apoptosis and subsequent efferocytosis are required for their full immunosuppressive effects in vivo, answering the long-standing question of how MSCs mediate therapeutic effects that persist beyond their survival.

Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies.


This is interesting (and also somewhat charming in that it's so bizarre), but ultimately: if the idea here is to induce aptosis/reduce inflammation, the benefits will be be on the order of calorie restriction and exercise right?

Posted by: Greg Schulte at November 18th, 2021 5:02 PM
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