Abstract
Mesenchymal stem cell (MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases, but its underlying mechanism has not been fully understood. Dead cells, including apoptotic cells have immunomodulatory properties. It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5~50% in the ongoing clinical trials. It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs. We found that the MSC therapeutic preparation in the present study had about 5% dead MSCs (DMSCs), characterized by apoptotic cells. Namely, 1 × 106 MSCs in the preparation contained about 5 × 104 DMSCs. We found that the treatment with even 5 × 104 DMSCs alone had the equal therapeutic effects as with 1 × 106 MSCs. This protective effect of the dead MSCs alone was confirmed in four mouse models, including concanavalin A (ConA)- and carbon tetrachloride (CCl4)-induced acute liver injury, LPS-induced lung injury and spinal cord injury. We also found that the infused MSCs died by apoptosis in vivo. Furthermore, the therapeutic effect was attributed to the elevated level of phosphatidylserine (PS) upon the injection of MSCs or DMSCs. The direct administration of PS liposomes (PSLs) mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs. The Mer tyrosine kinase (MerTK) deficiency or the knockout of chemokine receptor C–C motif chemokine receptor 2 (CCR2) reversed these protective effects of MSCs or DMSCs. These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the “living MSCs preparation” through releasing PS, which was further recognized by MerTK and participated in modulating immune cells.
Highlights
Mesenchymal stem cell (MSC)-based therapy has been recognized as a promising option for the life-threatening diseases such as acute myocardial injury, liver failure, lung injury, stroke, hematopoietic disorders, etc.[1,2,3,4,5,6] MSCs derived from the bone marrow, umbilical cord, or adipose tissue have the potential to differentiate into various cell lineages, replacing the damaged tissues,[7] which makes MSCs candidates for cell-based therapeutic strategies for certain diseases
The results showed that MSCs, dead MSCs (DMSCs), and PS liposomes (PSLs) attenuated liver injury compared with the phosphate buffer solution (PBS) group in WT mice, but these effects were eliminated in chemokine receptor 2 (CCR2)−/− mice (Fig. 7b–d)
In the set of experiments, we observed a significant increase in the level of PS after MSCs or DMSCs treatment
Summary
Mesenchymal stem cell (MSC)-based therapy has been recognized as a promising option for the life-threatening diseases such as acute myocardial injury, liver failure, lung injury, stroke, hematopoietic disorders, etc.[1,2,3,4,5,6] MSCs derived from the bone marrow, umbilical cord, or adipose tissue have the potential to differentiate into various cell lineages, replacing the damaged tissues,[7] which makes MSCs candidates for cell-based therapeutic strategies for certain diseases. Studies reported that MSCs possess immunomodulatory potential in both innate immunity and adaptive immunity, and MSCs regulate the functions of various immune cells through cell-to-cell contact and paracrine activity.[8,9] the molecular mechanisms of MSC-mediated immunomodulation remain unclear. Many previous studies hold the idea that implanted MSCs could reach to injured site and further regulate the immunemicroenvironment. It is reported that the therapeutic potentials of MSCs mainly attribute to the replacement of the damaged tissues by differentiating into various cell lineages and the secretion of regulating factors, including immunomodulatory factors, angiogenic factors, anti‐apoptotic factors, and antioxidative factors,[10,11] which are based on the viability of MSCs
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