Integrin and FAK Regulation of Human Pluripotent Stem Cells

Vitillo, Loriana; Kimber, Susan J.

doi:10.1007/s40778-017-0100-x

Cited by 52 publications

(36 citation statements)

References 83 publications

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“…Physical interactions with cells or the ECM can be transduced into biological signals and influence actin dynamics via mechanosensitive receptors, such as integrin receptors and GPCRs [70]. Evidence has shown that integrin heterodimers, α5β1, α6β1, and αvβ3, mediate interactions between ESCs and various ECM substrates [13,[71][72][73]; they also play an important role in the maintenance of pluripotency [74], and matrix stiffness regulates integrin binding [75]. Whereas GPCRs, including lysophosphatidic acid receptors (LPARs) and sphingosine-1-phosphate receptors (S1PRs), play a role in the YAP signaling axis.…”

Section: Discussionmentioning

confidence: 99%

Self-Assembling Scaffolds Supported Long-Term Growth of Human Primed Embryonic Stem Cells and Upregulated Core and Naïve Pluripotent Markers

McKee

Brown

Chaudhry

2019

Cells

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The maintenance and expansion of human embryonic stem cells (ESCs) in two-dimensional (2-D) culture is technically challenging, requiring routine manipulation and passaging. We developed three-dimensional (3-D) scaffolds to mimic the in vivo microenvironment for stem cell proliferation. The scaffolds were made of two 8-arm polyethylene glycol (PEG) polymers functionalized with thiol (PEG-8-SH) and acrylate (PEG-8-Acr) end groups, which self-assembled via a Michael addition reaction. When primed ESCs (H9 cells) were mixed with PEG polymers, they were encapsulated and grew for an extended period, while maintaining their viability, self-renewal, and differentiation potential both in vitro and in vivo. Three-dimensional (3-D) self-assembling scaffold-grown cells displayed an upregulation of core pluripotency genes, OCT4, NANOG, and SOX2. In addition, the expression of primed markers decreased, while the expression of naïve markers substantially increased. Interestingly, the expression of mechanosensitive genes, YAP and TAZ, was also upregulated. YAP inhibition by Verteporfin abrogated the increased expression of YAP/TAZ as well as core and naïve pluripotent markers. Evidently, the 3-D culture conditions induced the upregulation of makers associated with a naïve state of pluripotency in the primed cells. Overall, our 3-D culture system supported the expansion of a homogenous population of ESCs and should be helpful in advancing their use for cell therapy and regenerative medicine.

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Section: Discussionmentioning

confidence: 99%

Self-Assembling Scaffolds Supported Long-Term Growth of Human Primed Embryonic Stem Cells and Upregulated Core and Naïve Pluripotent Markers

McKee

Brown

Chaudhry

2019

Cells

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“…Integrins are important signaling receptors that mediate the interactions of the cells with extracellular matrix (24). They are involved in multiple inflammatory responses, including coronary atherosclerosis, obesity, etc.…”

Section: Discussionmentioning

confidence: 99%

“…*, p Ͻ 0.05. Integrin ␣ V ␤ 5 in M2 polarization transduction (24). The mechanism of the formation of integrin heterodimer has not been well-understood.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator–activated receptor γ (PPARγ) induces the gene expression of integrin αVβ5 to promote macrophage M2 polarization

Yao

Liu

Zhang

et al. 2018

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily and polarizes the macrophages into an anti-inflammatory M2 state. Integrins are transmembrane receptors that drive various cellular functions, including monocyte adhesion and foam cell formation. In this study, we first reported that the expression of integrins α and β was up-regulated by PPARγ activation in RAW264.7 cells and human peripheral blood monocytes. Luciferase reporter and ChIP assay revealed that PPARγ directly bound to the potential PPAR-responsive elements sites in the 5'-flanking regions of both murine and human integrin α and β genes, respectively. In addition, we showed that PPARγ augmented the ligation of integrins α and β Knockdown of integrin αβ by siRNA strategy or treatment with cilengitide, a potent inhibitor of integrin αβ, attenuated PPARγ-induced expression of Ym1 (chitinase-like protein 3), Arg1 (Arginase1), Fizz1 (resistin-like molecule RELMα), and other M2 marker genes, suggesting that the heterodimers of integrin αβ were involved in PPARγ-induced M2 polarization. In conclusion, these results provided novel evidence that PPARγ-mediated gene expression and the ensuing ligation of integrins α and β are implicated in macrophage M2 polarization.

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“…However, upregulation of select core pluripotent markers has been observed in 3-D culture of mouse [36,54] as well as human ESCs [55,56], suggesting a dependence on scaffold composition and culture conditions. We have reported upregulation of select naïve pluripotent markers in primed [37] and naïve human ESCs In both mouse and human ESCs, focal adhesion and integrin signaling serve pleiotropic roles in anchorage, contractility, survival, proliferation as well as support or inhibition of self-renewal [63]. Our study revealed upregulation in 3-D grown cells of several genes such as FLNC, COL4, CAV1, and SERPINE1, as well as ITGB1, ILK, and AKT1, which have been reported to be associated with actin cytoskeleton remodeling [64], and integrin mediated focal adhesion activation [65], respectively.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds

McKee

Brown

Bakshi

et al. 2020

Preprint

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Derivation of primed and naïve human embryonic stem cells (ESCs) have prompted an increased interest in devising culture conditions for maintaining their pluripotency and differential potential. Naïve ESCs are characterized by improved viability, proliferation, and differentiation capacity in comparison to primed ESCs. However, traditional two-dimensional (2-D) cell culture techniques fail to mimic the three-dimensional (3-D) in vivo microenvironment, which results in altered morphological and molecular characteristics of ESCs. Here, we describe the use of 3-D self-assembling scaffolds that support growth and maintenance of the naïve state characteristics of human ESC line, Elf1. Scaffolds were formed via a Michael addition reaction upon combination of two 8-arm polyethylene glycol (PEG) polymers functionalized with thiol (PEG-8-SH) and acrylate (PEG-8-Acr) end groups. 3-D scaffolds not only maintained the naïve state, but also supported long-term growth for up to 3 weeks without requiring routine passaging and manipulation. 3-D grown cells exhibited upregulation of core (OCT4, NANOG, and SOX2) and naïve (KLF17, KLF4, TFCP2L1, DPPA3, and DNMT3L) genes. These genes returned to normal levels when 3-D grown cells were propagated under 2-D culture conditions. Examination of RNA-sequencing demonstrated significant changes in gene expression profiles between 2-D and 3-D grown Elf1 cells. Gene Ontology analysis revealed upregulation of biological processes involved in the regulation of transcription and translation, as well as β-catenin-TCF complex assembly, extracellular matrix organization, and chromatin remodeling in 3-D grown Elf1 cells. 3-D culture conditions also induced upregulation of genes associated with several signaling pathways including Wnt signaling and focal adhesion. However, p53 signaling pathway associated genes were downregulated under these culture conditions. Our findings provide insight into the possible mechanisms of prolonged self-renewal as well as upregulation of pluripotent genes stimulated by the transduction of mechanical signals from the 3-D microenvironment.

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Integrin and FAK Regulation of Human Pluripotent Stem Cells

Cited by 52 publications

References 83 publications

Self-Assembling Scaffolds Supported Long-Term Growth of Human Primed Embryonic Stem Cells and Upregulated Core and Naïve Pluripotent Markers

Self-Assembling Scaffolds Supported Long-Term Growth of Human Primed Embryonic Stem Cells and Upregulated Core and Naïve Pluripotent Markers

Peroxisome proliferator–activated receptor γ (PPARγ) induces the gene expression of integrin αVβ5 to promote macrophage M2 polarization

Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds

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