More synergetic cooperation of Yamanaka factors in induced pluripotent stem cells than in embryonic stem cells

Huang, Jinyan; Chen, Taotao; Liu, Xiaosong; Jiang, Jing; Li, Jinsong; Li, Dangsheng; Liu, X Shirley; Li, Wei; Kang, Jiuhong; Pei, Gang

doi:10.1038/cr.2009.106

Cited by 47 publications

(32 citation statements)

References 37 publications

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“…CSF1 is known as macrophage colony stimulating factor 1, which regulates progenitor cell differentiation by AKT phosphorylation (27). KLF4, LIN28A, and NANOG are all well-known stem cell factors and reported to possess fundamental roles in iPS reprogramming, in which AKT and STAT3 pathways are activated to promote the induction of normal somatic cells to pluripotent stem cells (28,29). SNAIL (SNAI) is a zinc finger transcriptional repressor, which has been described to induce EMT via repression of ECadherin and activation of several signaling pathways, including STAT3 and AKT (30,31).…”

Section: Mir-128 Diminishes Mammary Carcinoma Cell Tumorinitiating Camentioning

confidence: 99%

Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells

Qian

Banerjee

et al. 2012

Cancer Research

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A discontinuous pattern of LOH at chromosome 3p has been reported in 87% of primary breast cancers. Despite the identification of several tumor suppressor genes in this region, there has yet to be a detailed analysis of noncoding RNAs including miRNAs in this region. In this study, we identified 16 aberrant miRNAs in this region and determined several that are frequently lost or amplified in breast cancer. miR-128-2 was the most commonly deleted miRNA. Embedded in the intron of the ARPP21 gene at chromosome 3p22.3, miR-128-2 was frequently downregulated along with ARPP21 in breast cancer, where it was negatively associated with clinicopathologic characteristics and survival outcome. Forced expression of miR-128 impeded several oncogenic traits of mammary carcinoma cells, whereas depleting miR-128-2 expression was sufficient for oncogenic transformation and stem cell-like behaviors in immortalized nontumorigenic mammary epithelial cells, both in vitro and in vivo. miR-128-2 silencing enabled transforming capacity partly by derepressing a cohort of direct targets (BMI1, CSF1, KLF4, LIN28A, NANOG, and SNAIL), which together acted to stimulate the PI3K/AKT and STAT3 signaling pathways. We also found that miR-128-2 was directly downregulated by SNAIL and repressed by TGF-b signaling, adding 2 additional negative feedback loops to this network. In summary, we have identified a novel TGF-b/SNAIL/miR-128 axis that provides a new avenue to understand the basis for oncogenic transformation of mammary epithelial cells. Cancer Res; 72(22); 6036-50. Ó2012 AACR.

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Section: Mir-128 Diminishes Mammary Carcinoma Cell Tumorinitiating Camentioning

confidence: 99%

Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells

Qian

Banerjee

et al. 2012

Cancer Research

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“…AA treatment induced cardiac differentiation of all tested cell lines originally without spontaneous development of beating cardiomyocytes ( Figure 4A). Further analyses were performed on three representative iPSC lines established by different laboratories [30][31][32]. The control EBs from all three lines showed no spontaneous contractility, whereas evident beating activities were reproducibly observed in AA-treated EBs with an increasing tendency from differentiation day 9-11 ( Figure 4B).…”

Section: Aa Treatment Rescues Innate Cardiogenic Deficiency Of Ipsc Lmentioning

confidence: 99%

Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells

et al. 2011

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Generation of induced pluripotent stem cells (iPSCs) has opened new avenues for the investigation of heart diseases, drug screening and potential autologous cardiac regeneration. However, their application is hampered by inefficient cardiac differentiation, high interline variability, and poor maturation of iPSC-derived cardiomyocytes (iPS-CMs). To identify efficient inducers for cardiac differentiation and maturation of iPSCs and elucidate the mechanisms, we systematically screened sixteen cardiomyocyte inducers on various murine (m) iPSCs and found that only ascorbic acid (AA) consistently and robustly enhanced the cardiac differentiation of eleven lines including eight without spontaneous cardiogenic potential. We then optimized the treatment conditions and demonstrated that differentiation day 2-6, a period for the specification of cardiac progenitor cells (CPCs), was a critical time for AA to take effect. This was further confirmed by the fact that AA increased the expression of cardiovascular but not mesodermal markers. Noteworthily, AA treatment led to approximately 7.3-fold (miPSCs) and 30.2-fold (human iPSCs) augment in the yield of iPS-CMs. Such effect was attributed to a specific increase in the proliferation of CPCs via the MEK-ERK1/2 pathway by promoting collagen synthesis. In addition, AA-induced cardiomyocytes showed better sarcomeric organization and enhanced responses of action potentials and calcium transients to β-adrenergic and muscarinic stimulations. These findings demonstrate that AA is a suitable cardiomyocyte inducer for iPSCs to improve cardiac differentiation and maturation simply, universally, and efficiently. These findings also highlight the importance of stimulating CPC proliferation by manipulating extracellular microenvironment in guiding cardiac differentiation of the pluripotent stem cells.

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“…Although Klf4 overexpression made OF more like mESCs, surprisingly, Klf4 also made OF less like iPSCs when not combined with Oct4, Sox2, and Nanog. Klf4 is known to associate with and co-occupy promoters of genes in a complex with Oct4 and Sox2 during reprogramming, but its expression is not limited to ESCs [47,48]. These data indicate that the effects of Klf4 on gene expression are not strictly stem cell-specific.…”

Section: Discussionmentioning

confidence: 88%

Induced Pluripotency and Oncogenic Transformation Are Related Processes

Riggs

Barrilleaux

Varlakhanova

et al. 2013

Stem Cells and Development

105

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Induced pluripotent stem cells (iPSCs) have the potential for creating patient-specific regenerative medicine therapies, but the links between pluripotency and tumorigenicity raise important safety concerns. More specifically, the methods employed for the production of iPSCs and oncogenic foci (OF), a form of in vitro produced tumor cells, are surprisingly similar, raising potential concerns about iPSCs. To test the hypotheses that iPSCs and OF are related cell types and, more broadly, that the induction of pluripotency and tumorigenicity are related processes, we produced iPSCs and OF in parallel from common parental fibroblasts. When we compared the transcriptomes of these iPSCs and OF to their parental fibroblasts, similar transcriptional changes were observed in both iPSCs and OF. A significant number of genes repressed during the iPSC formation were also repressed in OF, including a large cohort of differentiation-associated genes. iPSCs and OF shared a limited number of genes that were upregulated relative to parental fibroblasts, but gene ontology analysis pointed toward monosaccharide metabolism as upregulated in both iPSCs and OF. iPSCs and OF were distinct in that only iPSCs activated a host of pluripotency-related genes, while OF activated cellular damage and specific metabolic pathways. We reprogrammed oncogenic foci (ROF) to produce iPSC-like cells, a process dependent on Nanog. However, the ROF had reduced differentiation potential compared to iPSC, suggesting that oncogenic transformation leads to cellular changes that impair complete reprogramming. Taken together, these findings support a model in which OF and iPSCs are related, yet distinct cell types, and in which induced pluripotency and induced tumorigenesis are similar processes.

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More synergetic cooperation of Yamanaka factors in induced pluripotent stem cells than in embryonic stem cells

Cited by 47 publications

References 37 publications

Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells

Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells

Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells

Induced Pluripotency and Oncogenic Transformation Are Related Processes

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