Abstract
The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emerged as a viable candidate in the mouse. To explore the relationship between Dlk1-Dio3 expression and developmental potential more fully, we used murine ear mesenchymal stem cells (mEMSC) for iPS cell induction. Mouse EMSC are easily obtained and share functional characteristics with embryonic stem (ES) cells and therefore, may be a reliable non-embryonic source for iPS cell production. We report that mEMSC express high levels of Gtl2, a maternally expressed gene within the Dlk1-Dio3 imprinted cluster. Moreover, mEMSC produce Gtl2 expressing (Gtl2on) iPSC clones that share functional characteristics with ES cell clones. The production of Gtl2on iPS cell clones from mEMSC provides a new model with which to investigate the regulation of Dlk1-Dio3 cluster activity during direct cell reprogramming.
Highlights
Induced pluripotent stem cells have been produced from murine and human somatic cells by overexpression of defined factors [1,2,3]
An average of 30 induced pluripotent stem (iPS) colonies were detected from 1 × 105 Ear mesenchymal stem cells (EMSC) that were seeded in two independent experiments indicating a reprogramming efficiency of 0.03%
Ten mouse iPS (miPS) cell clones were established and the characterization of two representative lines, miPS01 and miPS02, are the basis for this study. Both miPS01 and miPS02 stained positive for the pluripotency markers alkaline phosphatase (AP), Oct4, Sox2, Nanog, Lin28 and SSEA-1 (Figure 1(d))
Summary
Induced pluripotent stem (iPS) cells have been produced from murine and human somatic cells by overexpression of defined factors [1,2,3]. These iPS cells share certain structural and functional characteristics with embryonic stem (ES) cells including similar epigenetic patterns [4,5], differentiation potential [2,6] and full-term development, as demonstrated by tetraploid complementation [7,8,9] Taken together, these data suggest that iPS cells, like ES cells, hold tremendous clinical promise for the treatment of disease, repair of damaged tissues and for drug discovery [10]. These data suggest that iPS cells, like ES cells, hold tremendous clinical promise for the treatment of disease, repair of damaged tissues and for drug discovery [10] Despite these similarities, there is growing evidence that iPS cells differ significantly from ES cells with respect to mRNA and microRNA (miRNA) expression patterns [11,12,13], chimera development and postnatal viability [3,14,15] and immunogenicity [16]. In order to realize the full clinical potential of iPS cells, it is imperative to more fully understand the mechanisms that drive somatic cell reprogramming with a view toward improving iPS cell production technology
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