Pluripotency Redux — Advances in Stem-Cell Research

A cell's ability to give to rise to all the cell types of the embryo and the adult organism is called pluripotency. Pluripotent cells are found within mammalian blastocysts and persist briefly in embryos after implantation. Embryonic stem cells, derived from the inner cell mass of blastocysts, are a renewable source of pluripotent stem cells that are proving valuable in basic science studies and may eventually become a source of cells for safe, effective cell-based therapies. Much embryonic stem-cell research has focused on determining the molecular signature of pluripotency, and a picture is emerging of a complex interaction among transcription factor networks, signaling pathways, and epigenetic processes involving modifications in the structure of DNA, histones, and chromatin.

Deciphering the molecular basis of pluripotency will facilitate the development of procedures for efficiently deriving patient-specific stem cells. In somatic-cell nuclear transfer, which has held the greatest promise for generating such cell lines, the nucleus of a somatic cell is introduced into an enucleated oocyte or mitotic zygote and is "reprogrammed" to an embryonic state, resulting in the formation of a blastocyst from which embryonic stem cells can be derived. Although this procedure has been demonstrated in animals, it has yet to be accomplished with human oocytes or zygotes. An alternative approach to reprogramming a somatic cell is to fuse it with an embryonic stem cell, but the resulting hybrid pluripotent cell is tetraploid and of limited practical application.

Against this background, a study published last year by Takahashi and Yamanaka¹ surprised and excited stem-cell biologists. Using a novel strategy, the investigators showed that fibroblasts derived from tissues of adult and fetal mice could be induced to become embryonic-stem-cell–like cells with the introduction of four genes expressing transcription factors. Twenty-four genes were initially chosen as candidates on the basis of their preferential expression in embryonic stem cells or their known roles in the maintenance of such cells or in cell-cycle regulation. These genes were introduced into fibroblasts isolated from mouse embryos and adult tail tips in a combinatorial manner through retroviral transduction.

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