Forced expression of Nanog in hematopoietic stem cells results in a γδT-cell disorder

Abstract

Nanog is a key molecule involved in the maintenance of the self-renewal of undifferentiated embryonic stem (ES) cells. In this work we investigate whether Nanog can enhance self-renewal in hematopoietic stem cells. Contrary to our expectation, no positive effect of Nanog transduction was detected in bone marrow reconstitution assays. However, recipients of Nanog-transduced (Nanog) hematopoietic stem cells (HSCs) invariantly develop a unique disorder typified by an atrophic thymus occupied by Nanogexpressing ␥␦T-cell receptor-positive (TCR ؉ ) cells (Nanog T cells). All thymi are eventually occupied by Nanog T cells with CD25 ؉ CD44 ؉ surface phenotype that home selectively to the thymus on transfer and suppress normal thymocyte development, which is partly ascribed to destruction of the microenvironment in the thymus cortex. Moreover, this initial disorder invariantly develops to a lymphoproliferative disorder, in which Nanog T cells undergo unlimited proliferation in the peripheral lymphoid tissues and eventually kill the host. This invariable end result suggests that Nanog is a candidate oncogene for ␥␦T-cell IntroductionThe self-renewal capacity and multipotency of embryonic stem (ES) cells can easily be maintained in culture. Several molecules have been implicated in the maintenance of these essential features of ES cells. Oct3/4 in association with the high mobility group (HMG) factor Sox2 is reported to be essential for self-renewal of ES cells, 1-3 and forced Nanog expression can maintain the immature state of ES cells in a LIF-Stat3-independent manner. 4,5 However, the exact molecular mechanism underlying the maintenance of the stem cell state is yet to be elucidated.Several reports have suggested that the core factors maintaining ES self-renewal can affect the activity of other stem cells. For example, Oct3/4 is expressed in mesenchymal stem cells derived from CD133 ϩ cells in mobilized peripheral blood and cord blood. 6 Nanog was also shown to be expressed in circulating CD14 ϩ CD34 low endothelial cells. 7 Although the role of these molecules in adult tissue stem cells remains unclear, it has been expected that it may be possible to use them to enhance the self-renewal of tissue stem cells. This expectation is supported by the recent report of Hochedlinger et al 8 showing that Oct3/4 overexpression enhances the proliferation of tissue stem cells.Compared with ES cells, it has been difficult to maintain the self-renewal of unmanipulated hematopoietic stem cells in vitro, although forced expression of HoxB4 or activated ␤-catenin confers enhanced self-renewal to hematopoietic progenitor cells (HPCs) in vitro. 9,10 Hence, it is worthwhile to determine whether the molecules involved in the self-renewal of ES cells can enhance that of HPCs. The initial aim of this work was to evaluate the effect of ectopic expression of Nanog on the behavior of hematopoietic stem cells. Although this expectation was not the case, we report here that Nanog overexpression induces an unusual ␥␦T-cell receptor-positive (TCR...

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

“…4a, Supplementary Table 1). In addition, the thymus was atrophic, which is consistent with the reported effect of Nanog overexpression in the hematopoietic system 30 . Alterations were also observed in the intestine (inflammation and Paneth cell mislocalization).…”

The Dark Side of Cellular Plasticity: Stem Cells in Development and Cancer

“…The breakthrough of Takahashi and Yamanaka (Takahashi and Yamanaka, 2006) showed that only 4 transcription factors ("four hits") were necessary for induction of pluripotency. Of note, the 4 transcription factors have been shown to play an oncogenic role in different contexts, and both c-Myc and Klf4 are well-known oncogenes Okita et al, 2007;Rowland et al, 2005;Tanaka et al, 2007). This is a clear evidence of the essential mechanistic link between reprogramming and cancer, and illustrates the fact that there are a certain number of genes/proteins that are strong enough so as to induce the change of expression patterns in a global manner affecting cellular identity.…”

Is iPS cell the panacea?

“…Moreover, the expression of Sox2 can be detected in human gastric carcinoma (29), stomach adenocarcinomas (30), pancreatic carcinoma (31), vater adenocarcinoma (32), malignant glioma (33), breast cancer (34), and brain tumors (35). Nanog has also been demonstrated that the forced expression in hematopoietic stem cells can give rise to T cell disorder (36). Klf4 is overexpressed in squamous cell carcinoma (37,38), and Klf4 seems to be involved in other cancer formation process.…”