Excess Reactive Oxygen Species Production Mediates Monoclonal Antibody-Induced Human Embryonic Stem Cell Death via Oncosis

Team Photo for Cell Death and Differentiation 2017 24(3): 546-558
From Left: Dr Andre Choo, Zheng Jiyun, Dr Paul Matsudaira, and Dr Tan Heng Liang


Jiyun Zheng 1, Tan Heng Liang 2, Paul Matsudaira 1,3, Andre Choo 2,4

1 Mechanobiology Institute, National University of Singapore, Singapore
2 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore
3 Department of Biological Science, Faculty of Science. National University of Singapore, Singapore
4 Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore

Published in Cell Death and Differentiation 2017 24(3): 546-558 (Online Version)



Monoclonal antibodies (mAbs) have been widely used in therapeutic applications to eliminate undesired cells via various mechanisms of action, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and programmed cell death (PCD). Besides the well-known Fc-dependent mechanisms, pathways of antibody-induced apoptosis are also extensively studied. However, few studies have reported the ability of mAbs to kill cells through an alternate form of programmed cell death, called oncosis.

In this study, a mAb, TAG-A1 (A1), was generated by our group and found to selectively kill residual undifferentiated human embryonic stem cells (hESC), thus preventing the risk of teratoma formation upon transplantation of differentiated cells derived from hESC. We revealed that A1 induces hESC death via oncosis, exhibiting the hallmarks of rapid cell death, plasma membrane damage, and cell swelling.

Mechanistically, A1-induced oncosis was initiated by binding of bivalent A1 to surface microvilli of hESC and dimerizing antigen receptors. Upon activation of death signaling, A1-treated hESC undergo microvilli degradation and homotypic adhesion at the early stage. This was followed by excess reactive oxygen species (ROS) production, which is upstream of massive actin re-organization, mitochondrial impairment, and severe plasma membrane damage. The ability to evoke excess ROS production via the Nox2 isoform of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is critical in the cell death pathway. Taken together, we propose a mechanistic model of A1-induced hESC death.

To our knowledge, this is the first mechanistic model for mAb-induced hESC oncosis, which reveals a previously unrecognized role for NADPH oxidase-derived ROS in mediating oncotic hESC death. Collectively with previously reported role of NADPH oxidase-derived ROS in GA101-induced lymphoma death, it might support that NADPH oxidase-derived ROS plays a central role in mediating mAb-induced oncosis in various types of cells. These findings in the cell death pathway may be exploited to improve the efficiency of A1 in eliminating undifferentiated hESC and to provide insights into the study of other mAb-induced cell death.