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Human embryonic stem cells express an immunogenic nonhuman sialic acid


Human embryonic stem cells (HESC) can potentially generate every body cell type, making them excellent candidates for cell- and tissue-replacement therapies. HESC are typically cultured with animal-derived 'serum replacements' on mouse feeder layers. Both of these are sources of the nonhuman sialic acid Neu5Gc, against which many humans have circulating antibodies. Both HESC and derived embryoid bodies metabolically incorporate substantial amounts of Neu5Gc under standard conditions. Exposure to human sera with antibodies specific for Neu5Gc resulted in binding of immunoglobulin and deposition of complement, which would lead to cell killing in vivo. Levels of Neu5Gc on HESC and embryoid bodies dropped after culture in heat-inactivated anti-Neu5Gc antibody–negative human serum, reducing binding of antibodies and complement from high-titer sera, while allowing maintenance of the undifferentiated state. Complete elimination of Neu5Gc would be likely to require using human serum with human feeder layers, ideally starting with fresh HESC that have never been exposed to animal products.

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Figure 1: Detection of Neu5Gc on HESC cultured under conventional conditions.
Figure 2: HESC stably expressing EGFP can remain undifferentiated when NHS is substituted for animal-derived culture medium components.
Figure 3: Effect of growth in NHS on Neu5Gc content of HESC and embryoid bodies.
Figure 4: Binding of 'natural' antibodies from sera of normal human donors to HESC.
Figure 5: Binding of complement C3b from human sera to HESC.

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Correspondence to Ajit Varki.

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Martin, M., Muotri, A., Gage, F. et al. Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nat Med 11, 228–232 (2005).

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