scholarly journals Distinct SoxB1 networks are required for naïve and primed pluripotency

2017 ◽  
Author(s):  
Andrea Corsinotti ◽  
Frederick C. K. Wong ◽  
Tülin Tatar ◽  
Iwona Szczerbinska ◽  
Florian Halbritter ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Functional Redundancy ◽  
Self Renewal ◽  
Cell Fate Decisions ◽  
Pluripotent State

AbstractDeletion of Sox2 from embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naïve pluripotency.

scholarly journals Distinct SoxB1 networks are required for naïve and primed pluripotency

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Andrea Corsinotti ◽  
Frederick CK Wong ◽  
Tülin Tatar ◽  
Iwona Szczerbinska ◽  
Florian Halbritter ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Self Renewal ◽  
Cell Fate Decisions ◽  
Pluripotent State

Deletion of Sox2 from mouse embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here, we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naïve pluripotency.

scholarly journals O-GlcNAcylation of Sox2 at threonine 258 regulates the self-renewal and early cell fate of embryonic stem cells

2021 ◽  
Author(s):  
Dong Keon Kim ◽  
Jang-Seok Lee ◽  
Eun Young Lee ◽  
Hansol Jang ◽  
Suji Han ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Rna Sequencing ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Cartilage Tissue ◽  
Sequencing Analysis ◽  
Post Translational Modification ◽  
Self Renewal ◽  
Cell Fate Decisions

AbstractSox2 is a core transcription factor in embryonic stem cells (ESCs), and O-GlcNAcylation is a type of post-translational modification of nuclear-cytoplasmic proteins. Although both factors play important roles in the maintenance and differentiation of ESCs and the serine 248 (S248) and threonine 258 (T258) residues of Sox2 are modified by O-GlcNAcylation, the function of Sox2 O-GlcNAcylation is unclear. Here, we show that O-GlcNAcylation of Sox2 at T258 regulates mouse ESC self-renewal and early cell fate. ESCs in which wild-type Sox2 was replaced with the Sox2 T258A mutant exhibited reduced self-renewal, whereas ESCs with the Sox2 S248A point mutation did not. ESCs with the Sox2 T258A mutation heterologously introduced using the CRISPR/Cas9 system, designated E14-Sox2TA/WT, also exhibited reduced self-renewal. RNA sequencing analysis under self-renewal conditions showed that upregulated expression of early differentiation genes, rather than a downregulated expression of self-renewal genes, was responsible for the reduced self-renewal of E14-Sox2TA/WT cells. There was a significant decrease in ectodermal tissue and a marked increase in cartilage tissue in E14-Sox2TA/WT-derived teratomas compared with normal E14 ESC-derived teratomas. RNA sequencing of teratomas revealed that genes related to brain development had generally downregulated expression in the E14-Sox2TA/WT-derived teratomas. Our findings using the Sox2 T258A mutant suggest that Sox2 T258 O-GlcNAc has a positive effect on ESC self-renewal and plays an important role in the proper development of ectodermal lineage cells. Overall, our study directly links O-GlcNAcylation and early cell fate decisions.

scholarly journals Rapid changes in morphogen concentration control self-organized patterning in human embryonic stem cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Idse Heemskerk ◽  
Kari Burt ◽  
Matthew Miller ◽  
Sapna Chhabra ◽  
M Cecilia Guerra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Nodal Signaling ◽  
Cell Fate Decisions ◽  
Self Organized ◽  
Rapid Changes

During embryonic development, diffusible signaling molecules called morphogens are thought to determine cell fates in a concentration-dependent way. Yet, in mammalian embryos, concentrations change rapidly compared to the time for making cell fate decisions. Here, we use human embryonic stem cells (hESCs) to address how changing morphogen levels influence differentiation, focusing on how BMP4 and Nodal signaling govern the cell-fate decisions associated with gastrulation. We show that BMP4 response is concentration dependent, but that expression of many Nodal targets depends on rate of concentration change. Moreover, in a self-organized stem cell model for human gastrulation, expression of these genes follows rapid changes in endogenous Nodal signaling. Our study shows a striking contrast between the specific ways ligand dynamics are interpreted by two closely related signaling pathways, highlighting both the subtlety and importance of morphogen dynamics for understanding mammalian embryogenesis and designing optimized protocols for directed stem cell differentiation.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see <xref ref-type="decision-letter" rid="SA1">decision letter</xref>).

Asxl1 ablation in mouse embryonic stem cells impairs neural differentiation without affecting self-renewal

2019 ◽  
Vol 508 (3) ◽  
pp. 907-913 ◽  
Author(s):  
SoJung An ◽  
Ui-Hyun Park ◽  
Seungtae Moon ◽  
Myengmo Kang ◽  
Hyesook Youn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Self Renewal

scholarly journals Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells

PLoS Biology ◽  
2009 ◽  
Vol 7 (7) ◽  
pp. e1000149 ◽  
Author(s):  
Tibor Kalmar ◽  
Chea Lim ◽  
Penelope Hayward ◽  
Silvia Muñoz-Descalzo ◽  
Jennifer Nichols ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Cell Fate Decisions ◽  
Nanog Expression ◽  
Mediate Cell

scholarly journals Epsins Regulate Mouse Embryonic Stem Cell Exit from Pluripotency and Neural Commitment by Controlling Notch Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Marina Cardano ◽  
Jacopo Zasso ◽  
Luca Ruggiero ◽  
Giuseppina Di Giacomo ◽  
Matteo Marcatili ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Notch Signaling ◽  
Neural Differentiation ◽  
Radial Glia ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Progenitors ◽  
Notch Activation

Epsins are part of the internalization machinery pivotal to control clathrin-mediated endocytosis. Here, we report that epsin family members are expressed in mouse embryonic stem cells (mESCs) and that epsin1/2 knockdown alters both mESC exits from pluripotency and their differentiation. Furthermore, we show that epsin1/2 knockdown compromises the correct polarization and division of mESC-derived neural progenitors and their conversion into expandable radial glia-like neural stem cells. Finally, we provide evidence that Notch signaling is impaired following epsin1/2 knockdown and that experimental restoration of Notch signaling rescues the epsin-mediated phenotypes. We conclude that epsins contribute to control mESC exit from pluripotency and allow their neural differentiation by appropriate modulation of Notch signaling.

Hematopoietic Development from Human Embryonic Stem Cells

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 11-16 ◽  
Author(s):  
Mickie Bhatia
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Cell Based Therapy

Abstract The most common human cell-based therapy applied today is hematopoietic stem cell (HSC) transplantation. HSCs can be defined by two essential properties: self-renewal and multilineage hematopoietic differentiation. These combined HSC properties allow them to differentiate into all blood cell types (multilineage) in a sustained manner for the lifetime of the animal, which requires their ability to make cellular copies of themselves (self-renewal). These features can be tested by transplantation from donor to recipient and provide a functional basis to define and identify HSCs. Currently, human bone marrow (BM), mobilized peripheral blood, and umbilical cord blood (CB) represent the major sources of transplantable HSCs, but their availability for use is limited by both quantity and compatibility. Although increasing evidence suggests that somatic HSCs can be expanded to meet current needs, their in vivo potential is concomitantly compromised after ex vivo culture. Pluripotent human embryonic stem cells (hESCs) may provide an alternative. hESCs possess indefinite proliferative capacity in vitro, and have been shown to differentiate into the hematopoietic cell fate, giving rise to erythroid, myeloid, and lymphoid lineages using a variety of differentiation procedures. In most cases, hESC-derived hematopoietic cells show similar clonogenic progenitor capacity and primitive phenotype to somatic sources of hematopoietic progenitors, but possess limited in vivo repopulating capacity when transplanted into immunodeficient mice. Although this suggests HSC function can be derived from hESCs, the efficiency and quality of these cells must be characterized using surrogate models for potential clinical applications.

scholarly journals Genetic control of pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

2021 ◽  
Author(s):  
Candice Byers ◽  
Catrina Spruce ◽  
Haley J. Fortin ◽  
Anne Czechanski ◽  
Steven C. Munger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Genetic Regulation ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Embryoid Bodies ◽  
Cell Fate Decisions

AbstractGenetically diverse pluripotent stem cells (PSCs) display varied, heritable responses to differentiation cues in the culture environment. By harnessing these disparities through derivation of embryonic stem cells (ESCs) from the BXD mouse genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, we demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. Upon transition to formative pluripotency using epiblast-like cells (EpiLCs), B6 quickly dissolves naïve networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naïve pluripotency with little bias in differentiation. Genetic mapping identifies 6 major trans-acting loci co-regulating chromatin accessibility and gene expression in ESCs and EpiLCs, indicating a common regulatory system impacting cell state transition. These loci distally modulate occupancy of pluripotency factors, including TRIM28, P300, and POU5F1, at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacts chromatin accessibility in ESCs; while in EpiLCs the same locus subsequently influences gene expression, suggesting early chromatin priming. Consequently, the distal gene targets of this locus are enriched for neurogenesis genes and were more highly expressed when cells carried B6 haplotypes at this Chr 12 locus, supporting genetic regulation of biases in cell fate. Spontaneous formation of embryoid bodies validated this with B6 showing a propensity towards neuroectoderm differentiation and D2 towards definitive endoderm, confirming the fundamental importance of genetic variation influencing cell fate decisions.

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