Prospects for designing 'universal' stem cell lines

Successful transplantation of conventional tissues between individuals requires matching of human leukocyte associated antigens (HLA), in order to prevent rejection. Although the same principles apply to tissues differentiated from embryonic stem (ES) cells, recent advances in gene delivery and genetic regulation have raised the prospect of engineering grafts with reduced levels of HLA expression. This strategy may mitigate the effects of extensive HLA polymorphism which restricts the availability of suitable donors and necessitates the maintenance of large donor registries. Here, we discuss the potential of employing RNA interference (RNAi) to knockdown HLA expression, enabling allogeneic cells to evade immune recognition. We discuss how lentivirus-mediated delivery of short hairpin RNAs (shRNA) targeting pan-class I and allele-specific HLA achieves efficient, dose- dependent reduction in surface HLA expression in human cells. Thus, by combining genetic engineering and regenerative medicine, RNAi-induced silencing of HLA expression has the potential to create histocompatibility-enhanced and, perhaps even, "universally" compatible cellular grafts.