Sadhna O Piryani1, Yiqun Jiao1, Angel Y F Kam1, Yang Liu2, Tuan Vo-Dinh2, Benny J Chen3, Nelson J Chao3, Phuong L Doan4. 1. Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina. 2. Department of Biomedical Engineering, Duke University, Durham, North Carolina; Department of Biomedical Engineering Chemistry, Duke University, Durham, North Carolina. 3. Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina; Duke Cancer Institute, Duke University, Durham, North Carolina. 4. Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina; Duke Cancer Institute, Duke University, Durham, North Carolina. Electronic address: phuong.doan@duke.edu.
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.
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.
Authors: Martin Illemann; Rikke Helene Løvendahl Eefsen; Nigel Charles Bird; Ali Majeed; Kell Osterlind; Ole Didrik Laerum; Warner Alpízar-Alpízar; Ida Katrine Lund; Gunilla Høyer-Hansen Journal: Mol Carcinog Date: 2015-01-15 Impact factor: 4.784
Authors: Chenkai Ma; Hong P T Nguyen; Jordan J Jones; Stanley S Stylli; Clarissa A Whitehead; Lucy Paradiso; Rodney B Luwor; Zammam Areeb; Eric Hanssen; Ellie Cho; Ulrich Putz; Andrew H Kaye; Andrew P Morokoff Journal: Int J Mol Sci Date: 2022-03-02 Impact factor: 5.923