Abstract

In 2006, Yamanaka and Takahashi electrified the scientific community by discovering that mouse somatic cells can be converted into embryonic stem cell-like cells by retroviral transduction of four transcription factors: Oct4, Sox2, Klf4, and c-Myc (OSKM). The first generation of mouse induced pluripotent stem (iPS) cells was incompletely reprogrammed, and failed to contribute to germline transmission. Nearly one year later, three groups, including Yamanaka’s, improved the reprogramming methodology and generated iPS cells that were in many respects, indistinguishable from ES cells, and also contributed to chimera formation and germline transmission. Shortly thereafter, the successful reprogramming of human somatic cells opened the gate for the development of patient-specific iPS cells for biomedical research and clinical application. Though human iPS cells resemble human ES cells in many aspects, the current iPS cell technologies showed several limitations for clinical usage. First, the efficiency of iPS cell generation is still low and the reprogramming process takes at least two weeks. Second, the virus-delivery of reprogramming factors introduces inconceivable risks of insertional mutagenesis in the genome. Third, given the various strategies for direct reprogramming, it remains difficult to assess the quality of iPS cells generated in each lab and for each patient. These issues should be addressed properly before any iPS cells could be translated into clinic. Here, we review recent progress in human iPS cell technologies, with a focus on the virus-free and integration-free iPS cell generation, which may lead towards the eventual goal of clinical applications.