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MSC-derived Extracellular Vesicles Battle Inflammation with Inflammation!

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Review of “Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation” from STEM CELLS by Stuart P. Atkinson

Clinical strategies hoping to exploit the immunomodulatory characteristics of mesenchymal stem cells (MSCs) have recently shifted their focus from the cells themselves to secreted extracellular vesicles (EVs). EVs come prepacked with various proteins and RNA species and may represent a far safer means of modulating the immune system and promoting tissue regeneration [1]. 

In a recent STEM CELLS study, researchers from the lab of Matthew T. Harting (University of Texas McGovern Medical School, USA) have employed a clinically relevant new system to collect and assess the potential of MSC-derived EVs. The application of this system now demonstrates that pretreatment of MSCs with proinflammatory cytokines may represent an efficient means to yield EVs with a more potent immunomodulatory capacity [2]. Can we battle inflammation with inflammation?

The study first collected and compared EVs from untreated bone marrow-derived MSCs and those pretreated with the TNF-α and IFN-γ proinflammatory cytokines employing a highly scalable and current Good Manufacturing Practice (cGMP)-compliant tangential flow filtration (TFF) system (See Figure below). While both sets of EVs remained morphologically similar and displayed similar patterns of surface markers, EVs from pretreated MSCs expressed an altered profile of inflammation-associated cytokines; increases in ICAM1, CXCL12, and CCL5 and decreases in IL-5, IL-6, IL-10, and IL-13). Furthermore, the two EV populations also contained altered protein and nucleic acid (e.g. miRNA) composition.

An assessment of EVs in an activated rat splenocyte cytokine inhibition assay [3] suggested that, as observed for treatment with parental MSCs, both EV populations displayed potent immunomodulatory properties; however, EVs derived from pretreated MSCs performed much better. Further analysis suggested that this might be due to the heightened expression of COX2/PGE2 in EVs and an altered pattern of immune cell interaction and an elevated EV uptake following immune cell stimulation.

Overall, this exciting study suggests that we can indeed battle inflammation with inflammation, and treatment with EVs derived from proinflammatory cytokine-pretreated MSCs may represent an efficient immunomodulatory strategy in a number of different indications where chronic inflammation represents an ongoing problem.

For more on EVs and their therapeutic potential, stay tuned to the Stem Cells Portal!

Discussion Points

  • What other mechanisms control the immunomodulatory properties of MSCs?
  • Will other more available MSC populations, such as adipose-derived MSCs, behave in a similar manner?
  • Will further assessments of differentially expressed miRNA species highlight other important mechanisms at play?

References

  1. Fischer UM, Harting MT, Jimenez F, et al., Pulmonary Passage is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First-Pass Effect. Stem Cells and Development 2008;18:683-692.
  2. Harting MT, Srivastava AK, Zhaorigetu S, et al., Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation. STEM CELLS 2018;36:79-90.
  3. Kota DJ, Prabhakara KS, Toledano-Furman N, et al., Prostaglandin E2 Indicates Therapeutic Efficacy of Mesenchymal Stem Cells in Experimental Traumatic Brain Injury. STEM CELLS 2017;35:1416-1430.