Differentiate or die

22 Dec 2009

An antibody that selectively kills off undifferentiated stem cells may improve their clinical usefulness

Fig. 1: Scanning electron micrographs of  untreated embryonic stem cells (ESCs) (top), and ESCs treated with mAb 84 (bottom). Extensive pore formation (arrows) in the cell membrane is an indicator of oncotic cell death.

Fig. 1: Scanning electron micrographs of  untreated embryonic stem cells (ESCs) (top), and ESCs treated with mAb 84 (bottom). Extensive pore formation (arrows) in the cell membrane is an indicator of oncotic cell death.

Reproduced, with permission, from Ref. 2 © 2009 John Wiley & Sons

A key aspect of the clinical promise of embryonic stem cells (ESCs) is their remarkable capacity to differentiate into any cell type depending on the instructions they receive. In principle, this ‘pluripotency’ means that they could be used for transplantation, acting as replacements for damaged or defective tissues. However, only ESCs that have been successfully reprogrammed into mature cells can safely be used for such applications, as undifferentiated pluripotent cells present a serious risk for formation of tumors such as teratomas.

Now, a surprising find from Andre Choo and co-workers at the A*STAR Bioprocessing Technology Institute in Singapore may provide a useful tool for grooming stem cells for transplantation. Choo and his team were seeking antibodies — immunological proteins that bind to target molecules with high specificity — that recognize ESC-specific proteins. “We were particularly focused on antibodies to surface markers because, apart from characterization, we could use the antibodies for purification,” he says. What they found, however, was an antibody called mAb 84 that binds to ESCs with remarkable specificity — and then kills them1.

Cells can die by entering the tightly controlled apoptotic programmed death pathway. Results from Choo’s team, however, suggested that mAb 84-bound ESCs die via a less structured process known as oncosis. The team has confirmed this, and clarified the mechanism behind this antibody’s deadly, but selective, effects2.

Cells undergoing apoptosis display distinctive characteristics, including DNA fragmentation and activation of protein-destroying caspase enzymes; neither was observed in mAb 84-treated cells. Instead, these cells showed extensive damage to their outer membranes, with widespread pore formation—effects typically seen in oncotic cell death (Fig. 1).

Choo and his co-workers also noted that mAb 84 induces abnormal clumping of its target protein, podocalyxin-like protein-1 (PODXL), which may in turn play a role in pore formation. Since antibody treatment also triggers partial disruption of the cytoskeleton—the protein framework that helps cells maintain their proper shape—the researchers hypothesize that this disruption may also contribute to PODXL clustering.

Although relatively little is known about PODXL function in ESCs, the data suggest that this marker is highly specific to pluripotent cells, and the team sees potential value in mAb 84 as a means for targeted elimination of undifferentiated ESCs. “We are focusing on understanding the mechanism involved in triggering the pore formation resulting in cell death, and its application to eliminate residual teratoma-forming ESCs after differentiation in order to make stem cell therapy safer,” he says.

The A*STAR-affiliated authors on this highlight are from the Bioprocessing Technology Institute (BTI).

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  1. Choo, A.B., Tan, H.L., Ang, S.N., Fong, W.J., Chin, A., Lo, J., Zheng, L., Hentze, H., Philp, R.J., Oh, S.K. et al. Selection against undifferentiated human embryonic stem cells by a cytotoxic antibody recognizing podocalyxin-like protein-1. Stem Cells 25, 1454–1463 (2008). 
  2. Tan, H.L., Fong, W.J., Lee, E.H., Yap, M. & Choo, A. mAb 84, a cytotoxic antibody that kills undifferentiated human embryonic stem cells via oncosis. Stem Cells 27, 1792–1801 (2009). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature