학술논문
Sensor macrophages derived from human induced pluripotent stem cells to assess pyrogenic contaminations in parenteral drugs.
Document Type
Academic Journal
Author
Abdin SM; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; Mansel F; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; Hashtchin AR; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; Stem Cell Modelling of Development & Disease Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Ackermann M; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.; Hansen G; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.; Becker B; Microbiological Safety, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.; Kick B; Department of Biosciences, School of Natural Sciences, Technical University of Munich, Garching, Germany.; Munich Institute of Biomedical Engineering, Technical University of Munich, Garching, Germany.; Pham N; Department of Biosciences, School of Natural Sciences, Technical University of Munich, Garching, Germany.; Munich Institute of Biomedical Engineering, Technical University of Munich, Garching, Germany.; Dietz H; Department of Biosciences, School of Natural Sciences, Technical University of Munich, Garching, Germany.; Munich Institute of Biomedical Engineering, Technical University of Munich, Garching, Germany.; Schaniel C; Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Institute for Regenerative Medicine, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Martin U; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, Hannover, Germany.; Regenerative Biology to Reconstructive Therapy (REBIRTH), Centre for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany.; Spreitzer I; Microbiological Safety, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.; Lachmann N; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.; Regenerative Biology to Reconstructive Therapy (REBIRTH), Centre for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany.
Source
Publisher: IOP Pub Country of Publication: England NLM ID: 101521964 Publication Model: Electronic Cited Medium: Internet ISSN: 1758-5090 (Electronic) Linking ISSN: 17585082 NLM ISO Abbreviation: Biofabrication Subsets: MEDLINE
Subject
Language
English
Abstract
Ensuring the safety of parenteral drugs before injection into patients is of utmost importance. New regulations around the globe and the need to refrain from using animals however, have highlighted the need for new cell sources to be used in next-generation bioassays to detect the entire spectrum of possible contaminating pyrogens. Given the current drawbacks of the Monocyte-Activation-Test (MAT) with respect to the use of primary peripheral blood mono-nuclear cells or the use of monocytic cell lines, we here demonstrate the manufacturing of sensor monocytes/macrophages from human induced pluripotent stem cells (iMonoMac), which are fully defined and superior to current cell products. Using a modern and scalable manufacturing platform, iMonoMac showed typical macrophage-like morphology and stained positive for several Toll like receptor (TLRs) such as TLR-2, TLR-5, TLR-4. Furthermore, iMonoMac derived from the same donor were sensitive to endotoxins, non-endotoxins, and process related pyrogens at a high dynamic range and across different cellular densities. Of note, iMonoMac showed increased sensitivity and reactivity to a broad range of pyrogens, demonstrated by the detection of interleukin-6 at low concentrations of LPS and MALP-2 which could not be reached using the current MAT cell sources. To further advance the system, iMonoMac or genetically engineered iMonoMac with NF- κ B-luciferase reporter cassette could reveal a specific activation response while correlating to the classical detection method employing enzyme-linked immunosorbent assay to measure cytokine secretion. Thus, we present a valuable cellular tool to assess parenteral drugs safety, facilitating the future acceptance and design of regulatory-approved bioassays.
(Creative Commons Attribution license.)
(Creative Commons Attribution license.)