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Spleens from mice exposed to either 9 Gy of whole-body ionizing radiation (WBIR) and WBIR combined with a 20% total body surface area burn (RCI) and treated with mouse mesenchymal stem cell derived extracellular vesicles (MSC-EVs)

ABSTRACT: Spleens from mice exposed to either 9 Gy of whole-body ionizing radiation (WBIR) and WBIR combined with a 20% total body surface area burn (RCI) and treated with mouse mesenchymal stem cell derived extracellular vesicles (MSC-EVs)

PROVIDER: PRJNA981144 | ENA |

REPOSITORIES: ENA

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Project description:Acute radiation syndrome (ARS) is a severe condition that develops after exposure to high doses of ionizing radiation that features immune suppression and organ failure. Currently, there are no diagnostics to identify the occurrence or severity of radiation exposure. There are also no current treatments or preventative strategies to mitigate ARS. Extracellular vesicles (EVs) are mediators of intercellular communication that contribute to immune dysfunction across diseases. We investigated if EV cargo would be able to identify whole body irradiation (WBIR) exposure and if EVs promote ARS immune dysfunction. We hypothesized that beneficial EVs derived from mesenchymal stem cells (MSC-EVs) would blunt ARS immune dysfunction and might serve as prophylactic radioprotectants. Mice received WBIR (2 or 9 Gy) with assessment of EVs at 3 and 7 days after exposure. LC-MS/MS proteomic analysis of WBIR-EVs found dose-related changes as well as candidate proteins that were increased with both doses and timepoints (34 total) such as Thromboxane-A Synthase and lymphocyte cytosolic protein 2. Suprabasin and Sarcalumenin were increased only after 9 Gy suggesting these proteins may indicate high dose/lethal exposure. Analysis of EV miRNAs identified miR-376 and miR-136, which were increased up to 200- and 60-fold respectively by both levels of WBIR and select miRNAs such as miR-1839 and miR-664 that were increased only with 9 Gy. WBIR-EVs (9 Gy) were biologically active and blunted immune responses to LPS in RAW264.7 macrophages, inhibiting canonical signaling pathways associated with wound healing and phagosome formation. Accordingly, WBIR-EVs also blunted RAW macrophage phagocytosis. When given 3 days after exposure, MSC-EVs slightly modified immune gene expression changes in the spleens of mice in response to WBIR and a combined radiation plus burn injury exposure (RCI). MSC-EVs normalized the expression of certain key immune genes such as NFκBia and Cxcr4 (WBIR), Map4k1, Ccr9 and Cxcl12 (RCI) lowered plasma TNFα cytokine levels after RCI, though most gene changes were not influenced. When given prophylactically (24 and 3 hours before exposure), MSC-EVs prolonged survival to the 9 Gy lethal exposure. Thus, EVs are important participants in ARS. EV cargo might be used to diagnose WBIR exposure, and MSC-EVs might serve as radioprotectants to blunt the impact of toxic radiation exposure.

Project description:Extracellular vesicles (EVs) are important paracrine mediators derived from various cells and biological fluids, including plasma, that are capable of inducing regenerative effects by transferring bioactive molecules such as microRNAs (miRNAs). This study investigated the effect of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) isolated from umbilical cord blood and human umbilical cord plasma-derived extracellular vesicles (UCB-EVs) on wound healing and scar formation reduction. Spatial transcriptomics (ST) was used to study the effects of MSC-EVs and UCB-EVs on the heterogeneity of major cell types and wound healing pathways in mouse skin tissue. MSC-EVs and UCB-EVs were isolated using ultracentrifugation and identified using transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of MSC-EVs and UCB-EVs on human dermal fibroblast-adult cell (HDF-a) migration and proliferation were evaluated using cell scratch assays, cell migration assays, and cell proliferation assays. In vivo, MSC-EVs and UCB-EVs were injected around full-cut wounds to evaluate their efficacy of wound healing by measuring wound closure rates and scar width and performing histological analysis. ST was performed on skin tissue samples from mice in each group after wound healing to analyze the heterogeneity of major cell types compared with the control group and investigate potential mechanisms affecting wound healing and scar formation. In vitro experiments demonstrated that MSC-EVs and UCB-EVs promoted the proliferation and migration of HDF-a cells. Local injection of MSC-EVs and UCB-EVs into the periphery of a mouse skin wound accelerated re-epithelialization, promoted wound healing, and reduced scar width. ST analysis of skin tissue from each group after wound healing revealed that MSC-EVs and UCB-EVs reduced the relative expression of marker genes in myofibroblasts, regulated wound healing, and decreased scar formation by reducing the expression of the TGF-β signaling pathway and increasing the expression of the Wnt signaling pathway. The results suggest that MSC-EVs and UCB-EVs play a significant role in the activity of cord blood plasma-derived mesenchymal stem cells and cord blood plasma. They can be considered promising new agents for promoting skin wound healing.

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Spleens from mice exposed to either 9 Gy of whole-body ionizing radiation (WBIR) and WBIR combined with a 20% total body surface area burn (RCI) and treated with mouse mesenchymal stem cell derived extracellular vesicles (MSC-EVs)

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