Imprinted gene expression, transplantation medicine, and the “other” human embryonic stem cell

Two types of embryonic stem cells are potentially useful as sources of therapeutic material in transplantation medicine. One type (EG cells) is derived from primordial germ cells taken from the developing gonadal ridges of human fetuses. The other (ES cells) is derived from the inner cell mass of blastocyst-stage preimplantation embryos. Both types of human stem cells are capable of long-term culture and proliferation in an undifferentiated state, and both are pluripotent when differentiated in vitro, giving rise to a wide variety of cells from many different lineages.

Recent work on mouse EG cells (1, 2) and ES cells (3, 4) has shown that stem cell-derived tissues and/or differentiated cells (i.e., the intended source of therapeutic material for transplantation) often fail to properly control the expression of imprinted genes (those genes that are expressed from only the maternal or only the paternal allele). Given the variety of imprinting-related developmental abnormalities observed in humans and experimental animals (reviewed in refs. 5 and 6), the possibility that imprinted gene expression might be dysregulated in stem cell-derived tissues raises a potentially serious problem for human stem cell transplantation therapy.

This problem has been confronted, directly, by Onyango et al. (7) in this issue of PNAS. These investigators examined the expression of four imprinted genes {IGF2, H19, SNRPN, and TSSC5 [also called SLC22A1L (see the OMIM database, MIM 602631, 3/8/2002, www.ncbi.nlm.nih.gov/omim/)]} in differentiated cells derived from three human EG cell lines. They observed transcription of only (or predominately, in the case of IGF2) a single allele in all informative cases. Although the investigators were not permitted to determine whether the transcribed allele was the “correct” allele (i.e., maternal for H19 and TSSC5, paternal for SNRPN and IGF2) under the terms of their Institutional Review Board approval, …