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Front Immunol. 2019 Nov 19;10:2685. doi: 10.3389/fimmu.2019.02685. eCollection 2019.

Preclinical Toxicity Evaluation of Clinical Grade Placenta-Derived Decidua Stromal Cells.

Author information

1
Translational Cell Therapy Research (TCR), Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
2
Department of Clinical Neuroscience, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
3
Department of Neuroradiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
4
Department of Radiopharmacy, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
5
Department of Nephrology and Internal Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie-Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
6
Berlin Institute of Health (BIH), Berlin, Germany.
7
Department of Transfusion Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie-Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
8
BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie-Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
9
Julius Wolff Institute (JWI), Charité-Universitätsmedizin Berlin, Corporate Member of Freie-Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
10
Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie-Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.

Abstract

Placenta-derived decidua stromal cells (DSCs) are being investigated as an alternative to other sources of mesenchymal stromal cells (MSCs) for cellular therapy. DSCs are more effective in treating acute inflammatory diseases in human and this is our preclinical safety study of human DSCs in Sprague-Dawley rats and Balb/c mice. Human DSCs were cultured and expanded from fetal membranes obtained from placentas following cesarean section. In rats, 0.5 × 106 cells/kg were injected intravenously (n = 4) or intra-aortal (n = 4). In mice, DSCs were given intravenously at doses ranging from 4-40 × 106 cells/kg (total of n = 120 mice). In vivo tracking of human cells in mice was performed by using transduced DSC with luciferin gene, and in rats by using 18F-FDG PET. Clotting parameters were determined in vitro and in vivo. All intra-arterially DSC-treated rats had normal motility and behavior and histological examination was normal for liver, spleen kidneys and thigh muscles. Mice treated with DSCs showed no immediate or long-term side effects. None of the mice died or showed acute toxicity or adverse reactions 3 and 30 days after DSC infusion. Murine blood biochemistry profiles related to liver, kidney, heart, and inflammatory indices was not influenced by DSC infusion and complete blood counts were normal. In vivo tracking of infused DSCs detected a signal in the lungs for up to 4 days post infusion. Compared to bone marrow derived MSCs, the DSCs had better viability, smaller size, but stronger clotting in human blood and plasma. Both MSC- and DSC-induced coagulation and complement activation markers, thrombin-anti-thrombin complex (TAT) and C3a, and in vitro clotting parameters were decreased by heparin supplementation. In conclusion, DSCs are safe with almost no side effects even with doses 40 times higher than are used clinically, particularly when supplemented with low-dose heparin.

KEYWORDS:

cellular therapy; mesenchymal stromal cells; placenta-derived decidua stromal cells; side effects; toxicity

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