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Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury.

ABSTRACT: PURPOSE:Extracellular vesicles (EVs) are shed vesicles that bear a combination of nucleic acids and proteins. EVs are becoming recognized as a mode of cell-to-cell communication. Because hematopoietic stem cells reside in proximity to endothelial cells (ECs), we investigated whether EC-derived EVs could regulate hematopoietic stem cell regeneration after ionizing radiation. METHODS AND MATERIALS:We generated EVs derived from primary murine marrow ECs. We sought to determine the response of irradiated hematopoietic stem and progenitor cells to syngeneic or allogeneic EVs in culture assays. Starting 24 hours after either sublethal or lethal irradiation, mice were treated with EVs or saline or cultured primary marrow endothelial cells to determine the hematopoietic response in vivo. RESULTS:We demonstrate that EVs bear nuclear material and express EC-specific markers. Treatment with EVs promoted cell expansion and increased the number of colony-forming units compared to irradiated, hematopoietic cell cultures treated with cytokines alone. After total body irradiation, EV-treated mice displayed preserved marrow cellularity, marrow vessel integrity, and prolonged overall survival compared with controls treated with saline. Treatment of irradiated hematopoietic stem/progenitor cells (HSPCs) with EVs from different genetic strains showed results similar to treatment of HSPCs from syngeneic EVs. Mechanistically, treatment of irradiated HSPCs with EVs resulted in decreased levels of annexin V+ apoptotic cell death, which is mediated in part by tissue inhibitor of metalloproteinase-1. CONCLUSIONS:Our findings show that syngeneic or allogeneic EVs could serve as cell-derived therapy to deliver physiologic doses of nucleic acids and growth factors to hematopoietic cells to accelerate hematopoietic regeneration.

SUBMITTER: Piryani SO

PROVIDER: S-EPMC6800133 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury.

Piryani Sadhna O SO Jiao Yiqun Y Kam Angel Y F AYF Liu Yang Y Vo-Dinh Tuan T Chen Benny J BJ Chao Nelson J NJ Doan Phuong L PL

International journal of radiation oncology, biology, physics 20190211 2

<h4>Purpose</h4>Extracellular vesicles (EVs) are shed vesicles that bear a combination of nucleic acids and proteins. EVs are becoming recognized as a mode of cell-to-cell communication. Because hematopoietic stem cells reside in proximity to endothelial cells (ECs), we investigated whether EC-derived EVs could regulate hematopoietic stem cell regeneration after ionizing radiation.<h4>Methods and materials</h4>We generated EVs derived from primary murine marrow ECs. We sought to determine the re ...[more]

PMID: 30763662

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Project description:The prevalence of arterial stiffness and hypertension increases with age. This study investigates the effect of induced pluripotent mesenchymal stem cell-derived extracellular vesicles (EVs) on ageing-associated arterial stiffness and hypertension. EVs were collected and purified from induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs). Young and old male C57BL/6 mice were used. Mice in the EVs group were injected via tail vein once a week for four weeks (18 x 106 EVs/mouse/injection). Blood pressure (BP) was measured using the tail-cuff method and validated by direct cannulation. Pulse wave velocity (PWV) was measured using a Doppler workstation. PWV and BP were increased significantly in the old mice, indicating arterial stiffness and hypertension. Intravenous administration of EVs significantly attenuated ageing-related arterial stiffness and hypertension, while enhancing endothelium-dependent vascular relaxation and arterial compliance in the old EVs mice. Elastin degradation and collagen I deposition (fibrosis) were increased in aortas of the old mice, but EVs substantially improved ageing-associated structural remodelling. Mechanistically, EVs abolished downregulation of sirtuin type 1 (SIRT1), and endothelial nitric oxide synthase (eNOS) protein expression in aortas of the older mice. In cultured human aortic endothelial cells, EVs promoted the expression of SIRT1, AMP-activated protein kinase alpha (AMPKα), and eNOS. In conclusion, iPS-MSC-derived EVs attenuated ageing-associated vascular endothelial dysfunction, arterial stiffness, and hypertension, likely via activation of the SIRT1-AMPKα-eNOS pathway and inhibition of MMPs and elastase. Thus, EVs mitigate arterial ageing. This finding also sheds light into the therapeutic potential of EVs for ageing-related vascular diseases.AbbreviationsEV: Extracellular vesicles; iPS: induced pluripotent stem cell; MSC: mesenchymal stem cell; AMPKα: AMP activated protein kinase α; eNOS: endothelial nitric oxide synthase; Sirt1: sirtuin 1; JNC7: Seventh Report of the Joint National Committee; CVD: cardiovascular disease; PWV: pulse wave velocity; BP: blood pressure; SNP: sodium nitroprusside.

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Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury.

Publications

Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury.

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