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Research on somatic cell reprogramming has progressed significantly over the past few decades, from nuclear transfer into frogs’ eggs in 1952 to the derivation of human-induced pluripotent stem (iPS) cells in the present day. In this article, I review five landmark papers that have laid the foundation for current efforts to apply somatic cell reprogramming in the clinic.
Recently, ectopic expression of four transcription factors (Oct4, Sox2, Klf4, c-Myc) was shown to reprogram somatic cells into induced pluripotent stem (iPS) cells, which have similar characteristics as embryonic stem (ES) cells : self-renewal and pluripotency. Successful reprogramming has excited the biomedical community because iPS cells have unprecedented potential in personalized cell-based therapy as well as in in vitro disease models. After reviewing the literature, I selected the five most important articles in the field of somatic cell reprogramming. Although there have been many excellent research articles published since the first demonstration of direct reprogramming of murine somatic cells , I have chosen reports that paved the way to these recent successes.
In this classic paper, Briggs and King showed that nuclei from Rana pipiens (Northern Leopard Frog) blastula cells undergo normal cleavage and develop into complete embryos when transplanted into enclosed oocytes . Gurdon and colleagues elaborated on this finding, reporting that even fully differentiated intestinal cells from Xenopus could be reprogrammed by frog oocytes . Although the efficiency of reprogramming was very low, these results demonstrated the important concept of cellular reprogramming by pluripotency-inducing factors in oocytes.
After noting spontaneous formation of testicular teratoma in the 129 mouse strain , Evans and Kaufman isolated embryonic carcinoma (EC) cells  and examined them for the basic characteristics of stem cells: pluripotency and self-renewing ability . Based on this research, the authors, together with Martin, succeeded in isolating embryonic stem (ES) cells from normally developing mouse blastocysts . This result not only facilitated future studies of mouse genetics, but also initiated the in vitro culturing of iPS cells.
After Briggs and King demonstrated the cell fate change using frog oocytes , somatic cell nuclear transfer (SCNT) was not successful in other species until 1997, when the sheep Dolly was cloned by Dr. Wilmut . In this pioneering paper, completely differentiated mammalian somatic cells were shown to become pluripotent after nuclear transfer into oocytes, giving rise to viable animals and allowing in-depth study of mammalian cell fate change .
After mouse ES cells were first isolated, nonhuman primate ES cells were derived and used to study primate tissue differentiation in vitro . However, this 1998 report demonstrated the first successful derivation of human ES cells . These human ES cells provided the opportunity to study human embryonic development and develop cell-based therapies for clinical use, as well as establishing a platform for the derivation of human iPS cells.
This landmark paper provided the first demonstration of direct reprogramming of mammalian cells using defined factors. Here, Takahashi and Yamanaka combined previous knowledge of murine ES cell cultures, the concept of pluripotency, and the plasticity of the mammalian genome to convert differentiated cellular fate to pluripotency by artificial overexpression of a set of genes. Specifically, they transduced Fbx15 reporter mouse fibroblasts with 24 candidate reprogramming genes . Fbx15 is only expressed in pluripotent stem cells, and so activation of Fbx15 in transduced cells indicated successful reprogramming. Remarkably, the introduction of only four transcription factors (Oct4, Sox2, Klf4, c-Myc) was sufficient to give rise to pluripotent cells, termed “induced pluripotent stem cells.”
Following Yamanaka’s original report on the derivation of murine iPS cells, successful generation of human iPS cells was reported by three independent groups that used a similar approach to express human versions of the four reprogramming factors in different combinations (OCT4, SOX2, NANOG, LIN28) [12-14]. Since then, there has been a ceaseless effort to 1) derive therapeutically safe iPS cells; 2) investigate the molecular mechanism of reprogramming; 3) improve reprogramming efficiency; and 4) establish an in vitro human disease model using iPS cells . Additionally, because the ultimate use of iPS cells lies in cell-replacement therapy, direct transdifferentiation into cells has been attracting more attention lately . Thanks to the foundational work of previous developmental, medical, and basic scientists, the direct reprogramming of cell fate change is possible and is making more exciting findings in stem cell research, including the successful treatment of patients using autologous iPS cells, possible.