Wnt5a Is Required for Endothelial Differentiation of Embryonic Stem Cells and Vascularization via Pathways Involving Both Wnt/β-Catenin and Protein Kinase Cα

Yang, Donghwa; Yoon, Jong Ho; Lee, Soung Hoon; Bryja, Vı́tězslav; Andersson, Emma R.; Arenas, Ernest; Kwon, Young Guen; Choi, Kang Yell

doi:10.1161/circresaha.108.185405

Cited by 63 publications

(57 citation statements)

References 45 publications

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“…Previous studies have shown that WNT signaling pathway played an important role in controlling morphogenesis in cardiac (4) and vascular (5) tissue development. WNT5a is a key signaling molecule that mediates endothelial cell proliferation and differentiation (5,29), while WNT11 plays an important role for cardiac development (4,30). Our results directly support the notion that the differential expression of these molecules within the EBs, potentially from nonmesoderm tissues, directly contributes to the differentiation of mesoderm precursors to either cardiac or endothelial pathways.…”

Section: Discussionsupporting

confidence: 79%

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Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11

Hwang

Chung

Ortmann

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

364

359

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Recently, various approaches for controlling the embryonic stem (ES) cell microenvironment have been developed for regulating cellular fate decisions. It has been reported that the lineage specific differentiation could be affected by the size of ES cell colonies and embryoid bodies (EBs). However, much of the underlying biology has not been well elucidated. In this study, we used microengineered hydrogel microwells to direct ES cell differentiation and determined the role of WNT signaling pathway in directing the differentiation. This was accomplished by forming ES cell aggregates within microwells to form different size EBs. We determined that cardiogenesis was enhanced in larger EBs (450 m in diameter), and in contrast, endothelial cell differentiation was increased in smaller EBs (150 m in diameter). Furthermore, we demonstrated that the EB-size mediated differentiation was driven by differential expression of WNTs, particularly noncanonical WNT pathway, according to EB size. The higher expression of WNT5a in smaller EBs enhanced endothelial cell differentiation. In contrast, the increased expression of WNT11 enhanced cardiogenesis. This was further validated by WNT5a-siRNA transfection assay and the addition of recombinant WNT5a. Our data suggest that EB size could be an important parameter in ES cell fate specification via differential gene expression of members of the noncanonical WNT pathway. Given the size-dependent response of EBs to differentiate to endothelial and cardiac lineages, hydrogel microwell arrays could be useful for directing stem cell fates and studying ES cell differentiation in a controlled manner.hydrogel microwells ͉ stem cell differentiation ͉ WNT signal pathway T he developmental versatility of embryonic stem (ES) cells offers a powerful approach for directing cell fate and is a promising source of progenitors for cell replacement therapy and tissue regeneration (1). ES cells can differentiate into a wide spectrum of cell types, such as cardiomyocytes and endothelial cells, by forming embryoid bodies (EBs) (2). Those lineages arise from distinct mesoderm subpopulations that develop sequentially from premesoderm cells (3). Such lineage specification is highly coordinated with differential changes in gene expression (4-8).Despite the therapeutic potential of ES cells, one of the significant challenges to their widespread clinical use, is the inability to homogeneously direct ES cell differentiation into specific lineages. One reason for the heterogeneity in EB differentiation is caused from variations in EB size (9, 10). To address this challenge for controlling the differentiation of ES cells, various microscale technologies (i.e., surface patterning, hydrogel microwells, and microfluidic systems) have been developed for directing the stem cell fate (11-15). Micropatterning techniques have been used to evaluate the effect of EB size on ES cell differentiation. For instance, microfabricated adhesive stencils were used to pattern ES cells for controlling initial ES cell aggregate sizes...

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Section: Discussionsupporting

confidence: 79%

“…Those lineages arise from distinct mesoderm subpopulations that develop sequentially from premesoderm cells (3). Such lineage specification is highly coordinated with differential changes in gene expression (4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11

Hwang

Chung

Ortmann

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

364

359

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“…Yang et al reported that Wnt5a is involved in the endothelial differentiation of ESCs via both Wnt/β-catenin and PKC signaling pathways and regulates embryonic vascular development. 93 Rho GTPases are involved in the self-renewal, multipotential differentiation ability, migration, and adhesion of stem cells. 94 In this study, F9 cells treated with RA or AgNPs showed upregulation of Rho expression, whereas the cells treated with RA or AgNPs plus cisplatin exhibited reduced expression of Rho, which confirms that cisplatin inhibits the AgNPs-induced Rho activation of differentiation in F9 cells.…”

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confidence: 99%

Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy

Han

Gurunathan

Choi

et al. 2017

IJN

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Background Silver nanoparticles (AgNPs) exhibit strong antibacterial and anticancer activity owing to their large surface-to-volume ratios and crystallographic surface structure. Owing to their various applications, understanding the mechanisms of action, biological interactions, potential toxicity, and beneficial effects of AgNPs is important. Here, we investigated the toxicity and differentiation-inducing effects of AgNPs in teratocarcinoma stem cells. Materials and methods AgNPs were synthesized and characterized using various analytical techniques such as UV–visible spectroscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, and transmission electron microscopy. The cellular responses of AgNPs were analyzed by a series of cellular and biochemical assays. Gene and protein expressions were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Results The AgNPs showed typical crystalline structures and spherical shapes (average size =20 nm). High concentration of AgNPs induced cytotoxicity in a dose-dependent manner by increasing lactate dehydrogenase leakage and reactive oxygen species. Furthermore, AgNPs caused mitochondrial dysfunction, DNA fragmentation, increased expression of apoptotic genes, and decreased expression of antiapoptotic genes. Lower concentrations of AgNPs induced neuronal differentiation by increasing the expression of differentiation markers and decreasing the expression of stem cell markers. Cisplatin reduced the viability of F9 cells that underwent AgNPs-induced differentiation. Conclusion The results showed that AgNPs caused differentially regulated cytotoxicity and induced neuronal differentiation of F9 cells in a concentration-dependent manner. Therefore, AgNPs can be used for differentiation therapy, along with chemotherapeutic agents, for improving cancer treatment by targeting specific chemotherapy-resistant cells within a tumor. Furthermore, understanding the molecular mechanisms of apoptosis and differentiation in stem cells could also help in developing new strategies for cancer stem cell (CSC) therapies. The findings of this study could significantly contribute to the nanomedicine because this study is the first of its kind, and our results will lead to new strategies for cancer and CSC therapies.

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“…Endothelial cells are active participants and regulators of inflammatory processes (15). Wnt5a has been implicated in endothelial proliferation and migration (16)(17)(18), as well as endothelial differentiation of embryonic stem cells (19).…”

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confidence: 99%

Wnt5a Induces Endothelial Inflammation via β-Catenin–Independent Signaling

Kim

et al. 2010

The Journal of Immunology

176

166

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Wnt5a Is Required for Endothelial Differentiation of Embryonic Stem Cells and Vascularization via Pathways Involving Both Wnt/β-Catenin and Protein Kinase Cα

Cited by 63 publications

References 45 publications

Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11

Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11

Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy

Wnt5a Induces Endothelial Inflammation via β-Catenin–Independent Signaling

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