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First published online September 7, 2006
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2005-0481v1
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Submitted on September 30, 2005
Accepted on August 29, 2006

Embryonic Stem Cells

Ablation of undifferentiated human embryonic stem cells: exploiting innate immunity against the Gal {alpha}1-3Gal{beta}1-4GlcNAc-R ({alpha}-gal) epitope

Zoe Hewitt 1, Helen Priddle 2, Alison Thomson 1, Davina Wojtacha 1, Jim McWhir 1*

1 Department of Gene Function and Development, Roslin Institute, Roslin, Midlothian, United Kingdom
2 Department of Gene Function and Development, Roslin Institute, Roslin, Midlothian, United Kingdom; Molecular Embryology and Stem Cell Lab, School of Human Development, Division of Obstetrics and Gynaecology, Queens Medical Centre, Nottingham, United Kingdom

* To whom correspondence should be addressed. E-mail: jim.mcwhir{at}bbsrc.ac.uk.


  Abstract

Although undifferentiated human ES cells (hESCs) are tumorigenic, this capacity is lost following differentiation, and hESCs are being widely investigated for applications in regenerative medicine. To engineer protection against the unintentional transplantation of undifferentiated cells, we generated hESCs carrying a construct in which the {alpha}1,3galactosyltransferase (GalT) open reading frame was transcribed from the hTERT promoter (pmGT). Since the endogenous GalT gene is inactive, GalT expression was limited to undifferentiated cells. A second chimaeric construct (pmfGT) differed by replacement of the GalT leader sequence for that of the fucosyl transferase gene. Two subclones containing stable integrations of pmGT and pmfGT respectively (M2 and F11) were assessed for their response to human serum containing antibodies to the Gal{alpha}1-3Gal{beta}1-4GlcNAc-R ({alpha}-gal) epitope. The low-variegation line, M2, and to a lesser extent the more variegated line F11, were sensitive to human serum when exposed in the undifferentiated state. However, M2 cells were largely insensitive following differentiation and retained both a normal karyotype and the ability to differentiate into derivatives of the 3 germ layers in SCID mice. These data exemplify a method of protection against residual, undifferentiated hESCs prior to engraftment and may provide ongoing immune surveillance post engraftment against dedifferentiation or against de novo tumorigenesis involving hTERT reactivation. Untransfected H9 cells were not sensitive to the human serum used in this study. Hence in our system, interactions of hESCs with other circulating antibodies such as anti-Neu5Gc, were not observed.

Key Words. regenerative medicine, selective ablation, Human embryonic stem cells, stem cell therapy, complement mediated lysis Gal ({alpha}1, 3) Galactosyltransferase




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