mTORC1 and mTORC2 play different roles in regulating cardiomyocyte differentiation from embryonic stem cells

Zheng, Bei; Wang, Jiadan; Tang, Leilei; Shi, Jiana; Zhu, Danyan

doi:10.1387/ijdb.160207dz

Cited by 12 publications

(12 citation statements)

References 39 publications

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“…It has also been revealed that the delayed replicative senescence in endothelial cells caused by inhibition of mTORC1 could be modulated by microRNAs through their influence on PTEN [ 104 , 105 ]. Finally, evidence has emerged indicating that mTOR may be involved in the maintenance of senescence in models of cardiomyocyte differentiation [ 106 , 107 , 108 ]. Thus, exposure of human cardiac progenitor cells to doxorubicin led to ROS accumulation and DDR activation, promoting cellular senescence [ 109 , 110 ].…”

Section: Mtorc1 Activity In Senescent Cellsmentioning

confidence: 99%

mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership

Cayo

Segovia

Venturini

et al. 2021

IJMS

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Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.

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Section: Mtorc1 Activity In Senescent Cellsmentioning

confidence: 99%

mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership

Cayo

Segovia

Venturini

et al. 2021

IJMS

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“…Rapamycin is an mTOR inhibitor and an autophagy inducer 33 . First, several studies reported that inhibition of mTORC1 by knockdown of RAPTOR promotes cardiac differentiation 59 ; however, inhibition of mTORC2 via knockdown of its component RICTOR suppresses cardiac differentiation 60 . Prolonged rapamycin treatment inhibits the assembly of mTORC2 31 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells

et al. 2020

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The mammalian target of rapamycin (mTOR) signaling pathway efficiently regulates the energy state of cells and maintains tissue homeostasis. Dysregulation of the mTOR pathway has been implicated in several human diseases. Rapamycin is a specific inhibitor of mTOR and pharmacological inhibition of mTOR with rapamycin promote cardiac cell generation from the differentiation of mouse and human embryonic stem cells. These studies strongly implicate a role of sustained mTOR activity in the differentiating functions of embryonic stem cells; however, they do not directly address the required effect for sustained mTOR activity in human cardiac progenitor cells. In the present study, we evaluated the effect of mTOR inhibition by rapamycin on the cellular function of human cardiac progenitor cells and discovered that treatment with rapamycin markedly attenuated replicative cell senescence in human cardiac progenitor cells (hCPCs) and promoted their cellular functions. Furthermore, rapamycin not only inhibited mTOR signaling but also influenced signaling pathways, including STAT3 and PIM1, in hCPCs. Therefore, these data reveal a crucial function for rapamycin in senescent hCPCs and provide clinical strategies based on chronic mTOR activity.

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“…The exact cause of death in Rictor-null embryos is not obvious but most probably arises due to defective fetal vascular development. In support of this assumption, there are data indicating the involvement of Rictor/mTORC2 in cardiomyocyte differentiation in mESCs in vitro [15,16]. Thus, mTORC1 predominantly functions in early development and mTORC2 is essential for later stages of differentiation until vascular development.…”

Section: The Mtor Pathway In Escsmentioning

confidence: 84%

The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy

et al. 2021

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Currently, the success of targeted anticancer therapies largely depends on the correct understanding of the dormant state of cancer cells, since it is increasingly regarded to fuel tumor recurrence. The concept of cancer cell dormancy is often considered as an adaptive response of cancer cells to stress, and, therefore, is limited. It is possible that the cancer dormant state is not a privilege of cancer cells but the same reproductive survival strategy as diapause used by embryonic stem cells (ESCs). Recent advances reveal that high autophagy and mTOR pathway reduction are key mechanisms contributing to dormancy and diapause. ESCs, sharing their main features with cancer stem cells, have a delicate balance between the mTOR pathway and autophagy activity permissive for diapause induction. In this review, we discuss the functioning of the mTOR signaling and autophagy in ESCs in detail that allows us to deepen our understanding of the biology of cancer cell dormancy.

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mTORC1 and mTORC2 play different roles in regulating cardiomyocyte differentiation from embryonic stem cells

Cited by 12 publications

References 39 publications

mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership

mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership

Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells

The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy

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