<i>Lefty1</i> and <i>Lefty2</i> Control the Balance Between Self-Renewal and Pluripotent Differentiation of Mouse Embryonic Stem Cells

Kim, Dae-Kwan; Cha, Young; Ahn, Hee-Jin; Kim, Gwangil; Park, Kyung-Soon

doi:10.1089/scd.2013.0220

Cited by 37 publications

(29 citation statements)

References 21 publications

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“…3A). These findings support the variability noted in the Lefty 1 and 2 ratio in the pluripotent differentiation of mouse ESCs, and during zebra fish embryo development [37,38].…”

Section: Fig 2 Characterization Of Differentiated Progenies Of Hescsupporting

confidence: 86%

Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation

Khalkhali‐Ellis

Galat

et al. 2016

Stem Cells and Development

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Lefty is a member of transforming growth factor-beta (TGF-b) superfamily and a potent antagonist of the TGFb/Nodal/Activin signaling pathway. Lefty is critical in sustaining self-renewal/pluripotency status, and implicated in the differentiation of embryonic stem cells (ESCs). However, emerging studies depict Lefty as a multifaceted protein involved in myriad cellular events. Lefty proteins (human Lefty A and B) are secreted glycoproteins, but their mode of secretion and the significance of their ''glycan'' moiety remain mostly unexplored. By employing an in vitro system of human ESCs (hESCs), we observed that Lefty protein(s) are encased in exosomes for extracellular release. The exosomal-and cell-associated Lefty diverge in their proteolytic processing, and possess N-glycan structures of high mannose and complex nature. Differentiation of hESCs to mesenchymal cells (MSCs) or neuronal progenitor cells (NPCs) entails distinct changes in the Lefty A/Lefty B gene(s), and protein expression. Specifically, the proteolytic cleavage and N-glycan composition of the cell-associated and exosomal Lefty differ in the differentiated progenies. These modifications affected Lefty's inhibitory effect on Nodal signaling in aggressive melanoma cells. The microheterogeneity in the processing and glycosylation of Lefty protein(s) between hESCs, MSCs, and NPCs could present efficient means of diversifying the endogenous functions of Lefty. Whether Lefty's diverse functions in embryonic patterning, as well as its diffusion range in the extracellular environment, are similarly affected remains to be determined. Our studies underscore the potential relevance of Lefty-packaged exosomes for combating debilitating diseases such as cancer.

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“…3A). These findings support the variability noted in the Lefty 1 and 2 ratio in the pluripotent differentiation of mouse ESCs, and during zebra fish embryo development [37,38].…”

Section: Fig 2 Characterization Of Differentiated Progenies Of Hescsupporting

confidence: 86%

Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation

Khalkhali‐Ellis

Galat

et al. 2016

Stem Cells and Development

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“…We also noted elevated levels of NODAL reinforcing the dependence of naïve hESCs on TGFβ/ActA signaling pathway to remain pluripotent. A recent study by Kim et al shows that Lefty1 and Lefty2 are crucial in maintaining the balance between pluripotency and differentiation in mESCs by regulating the TGFβ/ActA/Nodal signaling. They observed that Lefty1 knockdown resulted in mESC differentiation due to increased phosphorylation of Smad2 and Lefty2 knockdown resulted in decreased Smad2 phosphorylation and inefficient mESC differentiation.…”

Section: Resultsmentioning

confidence: 99%

Alternative Routes to Induce Naïve Pluripotency in Human Embryonic Stem Cells

et al. 2015

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Human embryonic stem cells (hESCs) closely resemble mouse epiblast stem cells exhibiting primed pluripotency unlike mouse ESCs (mESCs), which acquire a na€ ıve pluripotent state. Efforts have been made to trigger na€ ıve pluripotency in hESCs for subsequent unbiased lineage-specific differentiation, a common conundrum faced by primed pluripotent hESCs due to heterogeneity in gene expression existing within and between hESC lines. This required either ectopic expression of na€ ıve genes such as NANOG and KLF2 or inclusion of multiple pluripotency-associated factors. We report here a novel combination of small molecules and growth factors in culture medium (2i/LIF/basic fibroblast growth factor 1 Ascorbic Acid 1 Forskolin) facilitating rapid induction of transgene-free na€ ıve pluripotency in hESCs, as well as in mESCs, which has not been shown earlier. The converted na€ ıve hESCs survived long-term single-cell passaging, maintained a normal karyotype, upregulated na€ ıve pluripotency genes, and exhibited dependence on signaling pathways similar to na€ ıve mESCs. Moreover, they undergo global DNA demethylation and show a distinctive long noncoding RNA profile. We propose that in our medium, the FGF signaling pathway via PI3K/AKT/mTORC induced the conversion of primed hESCs toward na€ ıve pluripotency. Collectively, we demonstrate an alternate route to capture na€ ıve pluripotency in hESCs that is fast, reproducible, supports na€ ıve mESC derivation, and allows efficient differentiation. STEM CELLS 2015;33:2686-2698 SIGNIFICANCE STATEMENTNa€ ıve pluripotency, commonly displayed by mouse embryonic stem cells (ESCs), holds several advantages over stem cells exhibiting a primed pluripotent state such as human ESCs, which already show a bias towards certain lineages. We report the formulation of a novel culture condition with minimal components facilitating rapid, robust and efficient induction of na€ ıve pluripotency in primed human ESCs. These novel na€ ıve human ESCs were karyotypically normal, underwent efficient single cell passaging, exhibited a unique epigenetic and lncRNA profile and unbiased lineage-specific differentiation similar to mouse ESCs. This na€ ıve state of pluripotency is important for possible future regenerative cell applications including efficient genome engineering and targeted gene correction.

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“…One other notable effect of TBT was to increase expression of genes associated with controlling ESC renewal and germ layer and axis formation (LEFTY1, LEFTY2) [65, 66]. DUSP2, another regulator of cellular potency [67], was also elevated.…”

Section: Resultsmentioning

confidence: 99%

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

Midic

Vincent

VandeVoort

et al. 2016

Reproductive Toxicology

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Endocrine disrupting chemicals (EDCs) exert significant effects on health and physiology, many traceable to effects on stem cell programming underlying development. Understanding risk of low-level, chronic EDC exposure will be enhanced by knowledge of effects on stem cells. We exposed rhesus monkey embryonic stem cells to low levels of five EDCs [bisphenol A (BPA), atrazine (ATR), tributyltin (TBT), perfluorooctanoic acid (PFOA), and di-(2-ethylhexyl) phthalate (DEHP)] for 28 days, and evaluated effects on gene expression by RNAseq transcriptome profiling. We observed little effect of BPA, and small numbers of affected genes (≤119) with other EDCs. There was substantial overlap in effects across two, three, or four treatments. Ingenuity Pathway analysis indicated suppression of cell survival genes and genes downstream of several stress response mediators, activation of cell death genes, and modulations in several genes regulating pluripotency, differentiation, and germ layer development. Potential adverse effects of these changes on development are discussed.

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Lefty1 and Lefty2 Control the Balance Between Self-Renewal and Pluripotent Differentiation of Mouse Embryonic Stem Cells

Cited by 37 publications

References 21 publications

Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation

Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation

Alternative Routes to Induce Naïve Pluripotency in Human Embryonic Stem Cells

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

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