Cellular transplantation has enormous potential for treating a variety of degenerative or malignant conditions. While adult stem cells display limitations in expansion capacity and developmental potential, embryonic stem (ES) cells are an inexhaustable source of tissues for research and therapy. During the last decade, human ES cells have been isolated, and differentiated to several tissue-specific progenitors. In vitro differentiating ES cells recapitulate early steps of embryogenesis and often activate pathways that are conserved between mammals and developmental model systems such as fish and frog. Thus, exposure to morphogen gradients mimicking the embryonic environemnt can be exploited to pattern specific fate choices (e.g. blood), from in vitro differentiating ES cells.
However, immune barriers hinder the transplantation of ES-derived cellular therapies. Different strategies have been proposed for providing HLA-compatible (customized) pluripotent stem cells: 1) the establishment of HLA-matched ES cell banks, the generation of 2) genetically identical nuclear transfer ES cells or 3) histocompatible parthenogenetic ES cells, as well as, most recently, the generation of 4) induced pluripotent stem cells (iPS cells) via somatic cell reprogramming with defined genetic factors.
The generation of patient-specific autologous pluripotent stem cells may provide the opportunity to combine gene therapy with autologous cell therapy in the treatment of human genetic disease. Precise in situ gene repair can be performed via homologous recombination in cultured cells, followed by autologous tissue transplantation. This approach would circumvent the risks of insertional mutagenesis with viral vectors, as well as of Graft-Versus-Host-Disease following allogeneic transplantation. Although proof of principle experiments have been succesfully performed in murine model systems, a number of technical hurdles needs to be solved before human therapies based on pluripotent stem cells will enter clinical studies.