Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

Abstract

Mesenchymal stem cells show remarkable versatility and respond to extracellular and micro environmental cues by altering their phenotype and behavior. In this regard, the MSC’s immunomodulatory properties in tissue repair are well documented. The paracrine effects of MSCs in immunomodulation are, in part, attributable to their secreted extracellular vesicles (EVs). When MSCs migrate to the wound bed, they are exposed to a myriad of inflammatory signals. To understand their response to an inflammatory environment from an EV perspective, we sought to evaluate the effects of the inflammatory cytokine TNFα on MSC EV mediated immunomodulation. Our results indicate that while the physical characteristics of the EVs remain unchanged, the TNFα preconditioned MSC EVs possess enhanced immunomodulatory properties. In vitro experiments using polarized (M1 and M2) primary mouse macrophages indicated that the preconditioned MSC EVs suppressed pro-inflammatory (M1) markers such as IL-1β and iNOS and elevated reparatory (M2) markers such as Arg1 and CD206. When evaluated in vivo in a rat calvarial defect model, the TNFα preconditioned MSC EVs reduced inflammation at 1-, 3- and 7-days post wounding resulting in the subsequent enhanced bone formation at 4- and 8-weeks post wounding possibly by modulation of oncostatin M (OSM) expression. An analysis of EV miRNA composition revealed significant changes to anti-inflammatory miRNAs in the preconditioned MSC EVs hinting at a possible role for EV derived miRNA in the enhanced immunomodulatory activity. Overall, these results indicate that MSC exposure to inflammatory signals influence the MSC EV’s immunomodulatory function in the context of tissue repair. The specific function of TNFα preconditioned MSC EV miRNAs in immunomodulatory control of bone regeneration merits further investigation.

What Has Immunology Brought to Periodontal Disease in Recent Years?

“…Those vesicles containing any possible particles or substances play the role of intercellular mediators, and may act as a specific and precise regulator of the level of inflammatory response (Lin et al 2022 ). Similar data are presented in the study of Kang et al ( 2022 ), who studied the effect of TNF-α on mesenchymal stem cells, in particular the composition of mRNA in exosomes. The results of the study show that treating stem cells with TNF-α enhances immunomodulatory properties of mRNA contained in extracellular vesicles (Kang et al 2022 ).…”

“…Similar data are presented in the study of Kang et al ( 2022 ), who studied the effect of TNF-α on mesenchymal stem cells, in particular the composition of mRNA in exosomes. The results of the study show that treating stem cells with TNF-α enhances immunomodulatory properties of mRNA contained in extracellular vesicles (Kang et al 2022 ). A recent study reveals that a subtype of those cells, conditioned with curcumin, may significantly alter immune response.…”

Dentin Particulate for Bone Regeneration: An In Vitro Study

“…Exosomes could be used as biomimetic tools to induce migration, proliferation, and odontoblast-specific differentiation of stem cells in regenerative therapy. Based on this evidence, it is possible to speculate that dentin-based particles may have a positive effect on the differentiation of naïve cells, inducing them to produce exosomes that directly trigger odontoblastogenetic regeneration [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ].…”

Biomaterials and Extracellular Vesicle Delivery: Current Status, Applications and Challenges

“…The immune cells and mediators play important roles in mediating tissue homeostasis and reparative processes through a variety of orchestrated events and by being involved in inflammation, angiogenesis, and stem/progenitor cell activities such as proliferation and differentiation [ 277 , 278 , 279 ]. Similar to MSCs that have immunomodulatory functions, the immunomodulatory function associated with MSC-exosomes/EVs involves promoting the M2-like macrophage phenotype, Treg population, and TH2 immune responses [ 280 , 281 ]. Both immunomodulatory and proangiogenic factors were detected in MSC exosomes through proteomic profiling [ 282 ].…”