scholarly journals TPX2 Induces Mitotic Survival via BCL2L1 Induction Through YAP1 Protein Stabilization in Human Embryonic Stem Cells

2021 ◽  
Author(s):  
Yun-Jeong Kim ◽  
Young-Hyun Go ◽  
Ho-Chang Jeong ◽  
Seong-Min Kim ◽  
Hyun Sub Cheong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Copy Number ◽  
Embryonic Stem ◽  
Aurora A Kinase ◽  
High Tolerance ◽  
Mitotic Stress

Abstract Genetic alterations have been reported in most human embryonic stem cells (hESCs) for decades. ‘Survival advantage,’ a typical trait acquired during long-term in vitro culture, results from induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alteration via escape from mitotic stress. However, the underlying mechanisms for BCL2L1 induction remain undefined. Furthermore, abnormal mitosis and ‘survival advantage’ frequently occurring in the late passage are respectively associated with the expression of TPX2 and BCL2L1, which are located in locus 20q11.21. In this study, we observed that 20q11.21 CNV was not sufficient for BCL2L1 induction and consequent survival traits in pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. Inducible expression of TPX2 and basal TPX2 expression due to leakage of the inducible system in hESCs with normal copy number was sufficient to promote BCL2L1 expression and promoted high tolerance to mitotic stress. High Aurora A kinase activity by TPX2 stabilized YAP1 protein to promote YAP1 dependent BCL2L1 expression. Thus, a chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the aforementioned high tolerance to mitotic stress through BCL2L1 suppression. These results suggest that the collective expression of TPX2 and BCL2L1 from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling would promote genome instability during long-term in vitro hESC culture.

scholarly journals TPX2 Amplification-Driven Aberrant Mitosis in Long-Term Cultured Human Embryonic Stem Cells

2021 ◽  
Author(s):  
Ho-Chang Jeong ◽  
Young-Hyun Go ◽  
Joong-Gon Shin ◽  
Yun-Jeong Kim ◽  
Min-Guk Cho ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Mitotic Progression ◽  
Genome Wide ◽  
Hesc Culture ◽  
Spindle Stability

AbstractAlthough human embryonic stem cells (hESCs) are equipped with highly effective machinery for the maintenance of genome integrity, the frequency of genetic aberrations during long-term in vitro hESC culture has been a serious issue that raises concerns over their safety in future clinical applications. By passaging hESCs over a broad range of timepoints, we found that mitotic aberrations, such as the delay of mitosis, multipolar centrosomes, and chromosome mis-segregation, were increased in the late-passaged hESCs (LP-hESCs) in parallel with polyploidy compared to early-passaged hESCs (EP-hESCs). Through high-resolution genome-wide approaches and by following transcriptome analysis, we found that LP-hESCs with a minimal amplicon in chromosome 20q11.21 highly expressed TPX2 (targeting protein for Xklp2), a key protein for governing spindle assembly and cancer malignancy. Consistent with these findings, the inducible expression of TPX2 in EP-hESCs reproduced aberrant mitotic events, such as the delay of mitotic progression, spindle stability, misaligned chromosomes, and polyploidy. This data suggests that the amplification and increased transcription of the TPX2 gene at 20q11.21 could contribute to an increase in aberrant mitosis due to altered spindle dynamics.

scholarly journals Rapid Differentiation of Human Embryonic Stem Cells into Testosterone-Producing Leydig Cell-Like Cells In vitro

2021 ◽  
Author(s):  
Eun-Young Shin ◽  
Seah Park ◽  
Won Yun Choi ◽  
Dong Ryul Lee
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Male Hypogonadism ◽  
Testosterone Levels ◽  
Sequence Of Events ◽  
Short Period ◽  
Molecular Compounds

Abstract Background: Leydig cells (LCs) are testicular somatic cells that are the major producers of testosterone in males. Testosterone is essential for male physiology and reproduction. Reduced testosterone levels lead to hypogonadism and are associated with diverse pathologies, such as neuronal dysfunction, cardiovascular disease, and metabolic syndrome. LC transplantation is a promising therapy for hypogonadism; however, the number of LCs in the testis is very rare and they do not proliferate in vitro. Therefore, there is a need for an alternative source of LCs. Methods: To develop a safer, simple, and rapid strategy to generate human LC-like cells (LLCs) from stem cells, we first performed preliminary tests under different conditions for the induction of LLCs from human CD34/CD73 double positive-testis-derived stem cells (HTSCs). Based on the embryological sequence of events, we suggested a 3-step strategy for the differentiation of human ESCs into LLCs. We generated the mesendoderm in the first stage and intermediate mesoderm (IM) in the second stage and optimized the conditions for differentiation of IM into LLCs by comparing the secreted testosterone levels of each group. Results: HTSCs and human embryonic stem cells can be directly differentiated into LLCs by defined molecular compounds within a short period. Human ESC-derived LLCs can secrete testosterone and express steroidogenic markers. Conclusion: We developed a rapid and efficient protocol for the production of LLCs from stem cells using defined molecular compounds. These findings provide a new therapeutic cell source for male hypogonadism.

Nanofiber-Based in Vitro System for High Myogenic Differentiation of Human Embryonic Stem Cells

2013 ◽  
Vol 14 (12) ◽  
pp. 4207-4216 ◽  
Author(s):  
Matthew Leung ◽  
Ashleigh Cooper ◽  
Soumen Jana ◽  
Ching-Ting Tsao ◽  
Timothy A. Petrie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Myogenic Differentiation ◽  
Embryonic Stem ◽  
In Vitro System

Smooth-Muscle-Like Cells Derived from Human Embryonic Stem Cells Support and Augment Cord-Like Structures In Vitro

2010 ◽  
Vol 6 (2) ◽  
pp. 237-247 ◽  
Author(s):  
Elaine Vo ◽  
Donny Hanjaya-Putra ◽  
Yuanting Zha ◽  
Sravanti Kusuma ◽  
Sharon Gerecht
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem

Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3065-3075 ◽  
Author(s):  
Olena Klimchenko ◽  
Antonio Di Stefano ◽  
Birgit Geoerger ◽  
Sofiane Hamidi ◽  
Paule Opolon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Fetal Liver ◽  
Critical Role ◽  
Embryonic Stem ◽  
Blood Monocytes ◽  
Monocytic Cell ◽  
Monocytic Cells

Abstract The early emergence of macrophages and their large pattern of tissue distribution during development suggest that they may play a critical role in the initial steps of embryogenesis. In the present study, we show that monocytic cells derived from human embryonic stem cells (hESCs) and from fetal liver follow a differentiation pathway different to that of adult cells, leading to specific functions. Embryonic and fetal monocytic cells differentiated from a CD14lowCD16− precursor to form CD14highCD16+ cells without producing the CD14highCD16− cell population that predominates in adult peripheral blood. Both demonstrated an enhanced expression of genes encoding tissue-degrading enzymes, chemokines, and scavenger receptors, as was previously reported for M2 macrophages. Compared with adult blood monocytes, embryonic and fetal monocytic cells secreted high amounts of proteins acting on tissue remodeling and angiogenesis, and most of them expressed the Tie2 receptor. Furthermore, they promoted vascular remodeling in xenotransplanted human tumors. These findings suggest that the regulation of human fetal and embryonic monocytic cell differentiation leads to the generation of cells endowed mainly with anti-inflammatory and remodeling functions. Trophic and immunosuppressive functions of M2-polarized macrophages link fetus and tumor development, and hESCs offer a valuable experimental model for in vitro studies of mechanisms sustaining these processes.

Human embryonic stem cells rapidly take up and then clear exogenous human and animal prions in vitro

2011 ◽  
Vol 223 (5) ◽  
pp. 635-645 ◽  
Author(s):  
Zuzana Krejciova ◽  
Steve Pells ◽  
Enrico Cancellotti ◽  
Paz Freile ◽  
Matthew Bishop ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem
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