mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells

Zhou, Jiaxi; Su, Pei; Wang, Lu; Chen, Joanna; Zimmermann, Maike; Genbačev, Olga; Afonja, Olubunmi; Horne, Mary C.; Tanaka, Tetsuya; Duan, Enkui; Fisher, Susan J.; Liao, Jiayu; Chen, Jie; Wang, Fei

doi:10.1073/pnas.0901854106

Cited by 193 publications

(180 citation statements)

References 33 publications

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“…The mTOR pathway supports the long-term pluripotency of hESCs by inhibiting the expression of developmental and growth inhibitory-genes [22]. Furthermore, mTOR inhibition might affect the function of PA proteins before causing a decrease of their levels [22]. Inhibition of mTOR by rapamycin treatment for 3 days downregulated levels of PA proteins in hESCs (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, autophagy and the UPS may play different roles in regulating the homeostasis of PA proteins essential for maintaining pluripotency in hESCs. The mTOR pathway supports the long-term pluripotency of hESCs by inhibiting the expression of developmental and growth inhibitory-genes [22]. Furthermore, mTOR inhibition might affect the function of PA proteins before causing a decrease of their levels [22].…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, mTOR (mammalian target of rapamycin), which is a direct upstream signal regulating autophagy, is a critical regulator of hESC pluripotency [20][21][22]. Inhibition of mTOR downregulates PA genes, whereas it activates developmental genes in hESCs [22]. However, very little is known about the role of autophagy in the pluripotency of hESCs.…”

Section: Introductionmentioning

confidence: 99%

“…The mTOR signaling pathway associated with autophagy activity is known to be a key regulator in the pluripotency of hESCs 426 Homeostasis of PA Proteins Via Autophagy V C AlphaMed Press 2013 [20][21][22]. When hESCs were starved to inhibit mTOR signaling for 2.5 hours, mTOR-downstream markers (p-mTOR, p-S6K1, and p-4EBP) and PA proteins (OCT4, SOX2, and NANOG) were reduced, whereas the autophagy marker LC3 II was enhanced (Fig.…”

Section: Effects Of Autophagy Inhibition On the Regulation Of Pa Protmentioning

confidence: 99%

“…Thus, the intracellular homeostasis of respective PA proteins via de novo synthesis and degradation should be regulated to maintain the pluripotency of ESCs. Conversely, mTOR (mammalian target of rapamycin), which is a direct upstream signal regulating autophagy, is a critical regulator of hESC pluripotency [20][21][22]. Inhibition of mTOR downregulates PA genes, whereas it activates developmental genes in hESCs [22].…”

Section: Introductionmentioning

confidence: 99%

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Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Cho¹,

Han²,

Kim³

et al. 2014

Stem Cells

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The pluripotency of embryonic stem cells (ESCs) is maintained by intracellular networks of many pluripotency-associated (PA) proteins such as OCT4, SOX2, and NANOG. However, the mechanisms underlying the regulation of protein homeostasis for pluripotency remain elusive.Here, we first demonstrate that autophagy acts together with the ubiquitin-proteasome system (UPS) to modulate the levels of PA proteins in human ESCs (hESCs). Autophagy inhibition impaired the pluripotency despite increment of PA proteins in hESCs. Immunogold-electron microscopy confirmed localization of OCT4 molecules within autophagosomes. Also, knockdown of LC3 expression led to accumulation of PA proteins and reduction of pluripotency in hESCs. Interestingly, autophagy and the UPS showed differential kinetics in the degradation of PA proteins. Autophagy inhibition caused enhanced accumulation of both cytoplasmic and nuclear PA proteins, whereas the UPS inhibition led to preferentially degrade nuclear PA proteins. Our findings suggest that autophagy modulates homeostasis of PA proteins, providing a new insight in the regulation of pluripotency in hESCs. STEM CELLS 2014;32:424-435

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Effects Of Autophagy Inhibition On the Regulation Of Pa Protmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Cho¹,

Han²,

Kim³

et al. 2014

Stem Cells

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Effects of 3D microwell culture on growth kinetics and metabolism of human embryonic stem cells

Azarin

Larson

Almodóvar-Cruz

et al. 2012

Biotech and App Biochem

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Human embryonic stem cells (hESCs) hold potential in the field of tissue engineering given their capacity for both limitless self-renewal and differentiation to any adult cell type. However, several limitations, including the ability to expand undifferentiated cells and efficiently direct differentiation at scales needed for commercial cell production, prevent realizing the potential of hESCs in tissue engineering. Numerous studies have illustrated that 3-D culture systems provide microenvironmental cues that affect hESC pluripotency and differentiation fates, but little is known about how 3-D culture affects cell expansion. Here we have used a 3-D microwell array to model the differences in hESC growth kinetics and metabolism in 2-D vs. 3-D cultures. Our results demonstrated that 3-D microwell culture reduced hESC size and proliferative capacity, and impacted cell cycle dynamics, lengthening the G1 phase and shortening the G2/M phase of the cell cycle. However, glucose and lactate metabolism were similar in 2-D and 3-D cultures. Elucidating the effects of 3-D culture on growth and metabolism of hESCs may facilitate efforts for developing integrated, scalable cell expansion and differentiation processes with these cells.

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Biological functions of Elabela, a novel endogenous ligand of APJ receptor

Chen

Jiang

et al. 2018

Journal Cellular Physiology

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The G protein-coupled receptor APJ and its cognate ligand, apelin, are widely expressed throughout human body. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, fluid homeostasis, and energy metabolism regulation. Recently, a new endogenous peptidic ligand of APJ, named Elabela, has been identified and shown to play a crucial role in embryonic development. In addition, increasing evidences show that Elabela is also intimate associated with a large number of physiological processes in adulthood. However, a comprehensive summary of Elabela has not been reported to date. In this review, we provide an overview of the biological functions of Elabela. Collectively, Elabela, a potential therapeutic peptide, exerts diverse biological functions in both embryos and adult organisms, such as dysontogenesis, self-renewing of human embryonic stem cells, endoderm differentiation, heart morphogenesis, cardiac dyfunctions, blood pressure control, angiogenesis, blood pressure control, regulation of food and water intake, bone formation, and kidney diseases.

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mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells

Cited by 193 publications

References 33 publications

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Effects of 3D microwell culture on growth kinetics and metabolism of human embryonic stem cells

Biological functions of Elabela, a novel endogenous ligand of APJ receptor

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