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Induction of Immunogenic Cell Death in Lymphoma Cells by Wharton’s Jelly Mesenchymal Stem Cell Conditioned Medium

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Abstract

Strategies that induce immunogenic cell death (ICD) or downregulate CD47 or PD-L1 expression have resulted in successful therapeutic options for tumor eradication. Several groups have reported the tumoricidal effects of human umbilical cord Wharton’s jelly stem cells (hWJSCs) or its conditioned medium (hWJSC-CM) on certain cancers but the mechanisms have not been elucidated. Since hWJSCs possess immunomodulatory properties, we investigated whether one of the tumoricidal mechanisms was via ICD. We first concentrated hWJSC-CM into a 3 kDa concentrate and then exposed various concentrations of this concentrate to human lymphoma cells to find out which concentration had the greatest tumoricidal effect. We observed that a 500 µg/ml concentration of the concentrate had the greatest inhibitory effect. Thereafter, lymphoma cells were exposed to 500 µg/ml of the hWJSC-CM-3 kDa concentrate and then subjected to analysis for morphology, viability, apoptosis, mitochondrial and endoplasmic reticulum stress, danger associated molecular patterns (DAMP), extracellular HMGB1, CD47 and PD-L1 markers and dendritic cell phenotype. Extensive nuclear chromatin and mitochondrial changes with significantly decreased cell viability and increased apoptosis were observed in the treated lymphoma cells compared to controls. There were also significant increases in the release of DAMPs, extracellular HMGB1 and dendritic cell activation and maturation, with concomitant decreases in CD47 and PD-L1 expression in the treated cells compared to controls. In other ongoing studies we observed increased expression of specific tumor-suppressor molecules (miRNA-146a and miRNA-126, MCP-1, IL-6, IL-8 and IL-12) in hWJSC-CM suggesting that one or more of these molecules may be the modulators of the ICD.

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Acknowledgements

This work was supported by the Singapore National University Health System (NUHS) Aspiration Fund (New Idea) (R-174-000-155-720) research grant.

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  1. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Kent Ridge, Singapore, 119228, Singapore

    Daniel Hao Lin, Arijit Biswas, Mahesh Choolani, Chui-Yee Fong & Ariff Bongso

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  1. Daniel Hao Lin
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  2. Arijit Biswas
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  4. Chui-Yee Fong
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Contributions

DHL: Conception and design, executed the experiments, collection and assembly of data, analysis and interpretation, manuscript writing. ABi: Sought written informed consent from patients, obtained IRB approval for study, collection of human umbilical cords. MC: Data analysis and interpretation, scientific input. CYF: Conception and design, analysis and interpretation, scientific input, helped to obtain financial support. ABo: Conception and design, analysis and interpretation, manuscript correction and final approval, obtained financial support, Principal Investigator of the grant.

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Correspondence to Ariff Bongso.

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Lin, D.H., Biswas, A., Choolani, M. et al. Induction of Immunogenic Cell Death in Lymphoma Cells by Wharton’s Jelly Mesenchymal Stem Cell Conditioned Medium. Stem Cell Rev and Rep 13, 801–816 (2017). https://doi.org/10.1007/s12015-017-9767-8

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