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Yale J Biol Med. 2010 September; 83(3): 135–137.
Published online 2010 September.
PMCID: PMC2946127

Five Classic Articles in Somatic Cell Reprogramming

Abstract

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 [1]: 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 [1], I have chosen reports that paved the way to these recent successes.

Briggs R, King TJ. Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proc Natl Acad Sci USA. 1952;38(5):455-63

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 [2]. Gurdon and colleagues elaborated on this finding, reporting that even fully differentiated intestinal cells from Xenopus could be reprogrammed by frog oocytes [3]. Although the efficiency of reprogramming was very low, these results demonstrated the important concept of cellular reprogramming by pluripotency-inducing factors in oocytes.

Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154-6

After noting spontaneous formation of testicular teratoma in the 129 mouse strain [4], Evans and Kaufman isolated embryonic carcinoma (EC) cells [5] and examined them for the basic characteristics of stem cells: pluripotency and self-renewing ability [6]. Based on this research, the authors, together with Martin, succeeded in isolating embryonic stem (ES) cells from normally developing mouse blastocysts [7]. This result not only facilitated future studies of mouse genetics, but also initiated the in vitro culturing of iPS cells.

Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997;385(6619):810-3

After Briggs and King demonstrated the cell fate change using frog oocytes [2], somatic cell nuclear transfer (SCNT) was not successful in other species until 1997, when the sheep Dolly was cloned by Dr. Wilmut [8]. 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 [9].

Thomson JA, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-7

After mouse ES cells were first isolated, nonhuman primate ES cells were derived and used to study primate tissue differentiation in vitro [10]. However, this 1998 report demonstrated the first successful derivation of human ES cells [11]. 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.

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-72

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 [1]. 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 [15]. Additionally, because the ultimate use of iPS cells lies in cell-replacement therapy, direct transdifferentiation into cells has been attracting more attention lately [16]. 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.

Abbreviations

iPS
induced pluripotent stem
ES
embryonic stem
EC
embryonic carcinoma
SCNT
somatic cell nuclear transfer

References

  • Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–676. [PubMed]
  • Briggs R, King TJ. Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proc Natl Acad Sci USA. 1952;38(5):455–463. [PubMed]
  • Gurdon JB, Elsdale TR, Fischberg M. Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature. 1958;182(4627):64–65. [PubMed]
  • Stevens LC, Little CC. Spontaneous Testicular Teratomas in an Inbred Strain of Mice. Proc Natl Acad Sci USA. 1954;40(11):1080–1087. [PubMed]
  • Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–156. [PubMed]
  • Kleinsmith LJ, Pierce GB Jr. Multipotentiality of Single Embryonal Carcinoma Cells. Cancer Res. 1964;24:1544–1551. [PubMed]
  • Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981;78(12):7634–7638. [PubMed]
  • Campbell KH, McWhir J, Ritchie WA, Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature. 1996;380(6569):64–66. [PubMed]
  • Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997;385(6619):810–813. [PubMed]
  • Thomson JA, Kalishman J, Golos TJ, Durning M, Harris CP, Becker RA. et al. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA. 1995;92(17):7844–7848. [PubMed]
  • Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS. et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–1147. [PubMed]
  • Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451(7175):141–146. [PubMed]
  • Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–872. [PubMed]
  • Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–1920. [PubMed]
  • Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development. 2009;136(4):509–523. [PubMed]
  • Graf T, Enver T. Forcing cells to change lineages. Nature. 2009;462(7273):587–594. [PubMed]

Articles from The Yale Journal of Biology and Medicine are provided here courtesy of Yale Journal of Biology and Medicine