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Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial.
Stem Cells 2018; 36(11):1778-1788SC

Abstract

In experimental models, mesenchymal stem cells (MSCs) can modulate various immune responses implicated in the pathogenesis of sepsis. Intravenous injection of lipopolysaccharide (LPS) into healthy subjects represents a model with relevance for the host response to sepsis. To explore the use of MSCs in sepsis, we determined their effect on the response to intravenous LPS in a randomized study in 32 healthy subjects with four treatment arms: placebo or allogeneic adipose MSCs (ASCs) intravenously at either 0.25 × 106 , 1 × 106 , or 4 × 106 cells/kg; all subjects received LPS intravenously (2 ng/kg) one hour after the end of ASC infusion (Trial Register number 2014-002537-63, clinicaltrials.gov identifier NCT02328612). Infusion of ASCs was well tolerated. The high ASC dose increased the febrile response, exerted mixed pro-inflammatory (enhanced interleukin-8 and nucleosome release) and anti-inflammatory effects (increased interleukin-10 and transforming growth factor-β release), and enhanced coagulation activation and reduced the fibrinolytic response. Blood leukocyte transcriptome analyses showed a biphasic effect of ASCs on the LPS response: at 2 hours post LPS, ASC-infused subjects displayed higher expression of genes involved in innate immune pathways, whereas at 4 hours post LPS these subjects had lower expression of innate immune pathway genes. Infusion of ASCs did not modify the "ex vivo" responsiveness of whole blood to various bacterial agonists. These results indicate that intravenous infusion of allogeneic ASCs (4 × 106 cells/kg) has a variety of proinflammatory, anti-inflammatory, and procoagulant effects during human endotoxemia. Further studies are needed to assess the safety and efficacy of ASCs in sepsis patients. Stem Cells 2018;36:1778-1788.

Authors+Show Affiliations

Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Department of Experimental Immunology & Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Department of Pharmacy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.TiGenix SAU, Madrid, Spain.TiGenix SAU, Madrid, Spain.TiGenix SAU, Madrid, Spain.TiGenix NV, Leuven, Belgium.TiGenix SAU, Madrid, Spain.Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30063804

Citation

Perlee, Desiree, et al. "Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: a Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial." Stem Cells (Dayton, Ohio), vol. 36, no. 11, 2018, pp. 1778-1788.
Perlee D, van Vught LA, Scicluna BP, et al. Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial. Stem Cells. 2018;36(11):1778-1788.
Perlee, D., van Vught, L. A., Scicluna, B. P., Maag, A., Lutter, R., Kemper, E. M., ... van der Poll, T. (2018). Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial. Stem Cells (Dayton, Ohio), 36(11), pp. 1778-1788. doi:10.1002/stem.2891.
Perlee D, et al. Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: a Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial. Stem Cells. 2018;36(11):1778-1788. PubMed PMID: 30063804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial. AU - Perlee,Desiree, AU - van Vught,Lonneke A, AU - Scicluna,Brendon P, AU - Maag,Anja, AU - Lutter,René, AU - Kemper,Elles M, AU - van 't Veer,Cornelis, AU - Punchard,Marie A, AU - González,Jesús, AU - Richard,Marie Paule, AU - Dalemans,Wilfried, AU - Lombardo,Eleuterio, AU - de Vos,Alex F, AU - van der Poll,Tom, Y1 - 2018/08/20/ PY - 2018/02/21/received PY - 2018/06/06/revised PY - 2018/07/02/accepted PY - 2018/8/1/pubmed PY - 2019/11/27/medline PY - 2018/8/1/entrez KW - Adipose stem cells KW - Cellular therapy KW - Clinical trials KW - Mesenchymal stem cells SP - 1778 EP - 1788 JF - Stem cells (Dayton, Ohio) JO - Stem Cells VL - 36 IS - 11 N2 - In experimental models, mesenchymal stem cells (MSCs) can modulate various immune responses implicated in the pathogenesis of sepsis. Intravenous injection of lipopolysaccharide (LPS) into healthy subjects represents a model with relevance for the host response to sepsis. To explore the use of MSCs in sepsis, we determined their effect on the response to intravenous LPS in a randomized study in 32 healthy subjects with four treatment arms: placebo or allogeneic adipose MSCs (ASCs) intravenously at either 0.25 × 106 , 1 × 106 , or 4 × 106 cells/kg; all subjects received LPS intravenously (2 ng/kg) one hour after the end of ASC infusion (Trial Register number 2014-002537-63, clinicaltrials.gov identifier NCT02328612). Infusion of ASCs was well tolerated. The high ASC dose increased the febrile response, exerted mixed pro-inflammatory (enhanced interleukin-8 and nucleosome release) and anti-inflammatory effects (increased interleukin-10 and transforming growth factor-β release), and enhanced coagulation activation and reduced the fibrinolytic response. Blood leukocyte transcriptome analyses showed a biphasic effect of ASCs on the LPS response: at 2 hours post LPS, ASC-infused subjects displayed higher expression of genes involved in innate immune pathways, whereas at 4 hours post LPS these subjects had lower expression of innate immune pathway genes. Infusion of ASCs did not modify the "ex vivo" responsiveness of whole blood to various bacterial agonists. These results indicate that intravenous infusion of allogeneic ASCs (4 × 106 cells/kg) has a variety of proinflammatory, anti-inflammatory, and procoagulant effects during human endotoxemia. Further studies are needed to assess the safety and efficacy of ASCs in sepsis patients. Stem Cells 2018;36:1778-1788. SN - 1549-4918 UR - https://www.unboundmedicine.com/medline/citation/30063804/Intravenous_Infusion_of_Human_Adipose_Mesenchymal_Stem_Cells_Modifies_the_Host_Response_to_Lipopolysaccharide_in_Humans:_A_Randomized_Single_Blind_Parallel_Group_Placebo_Controlled_Trial_ L2 - https://doi.org/10.1002/stem.2891 DB - PRIME DP - Unbound Medicine ER -