The axis of mTOR-mitochondria-ROS and stemness of the hematopoietic stem cells

Chen, Chong; Liu, Yu; Liu, Yang; Zheng, Pan

doi:10.4161/cc.8.8.8139

Cited by 59 publications

(48 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When contact-inhibited fibroblasts were ROS, as well as increased mitochondrial mass and mitochondrial DNA copy number. 196,197,209 Antioxidant treatment also significantly rescued the ability of the Tsc1 -/-HSCs to reconstitute blood. Rapamycin treatment and siRNAs against mTOR binding partners causes decreased mitochondrial polarization, oxygen consumption and ATP production.…”

Section: Quiescence In Fibroblastsmentioning

confidence: 99%

Staying alive

et al. 2012

View full text Add to dashboard Cite

Ensuring the continuity of life requires that individual cells and entire organisms can survive not only in ideal environments, but also in conditions of scarcity. When conditions are unfavorable for proliferation, many cells have the capacity to enter a nondividing state, sometimes for years, while retaining their ability to reenter the proliferative cell cycle. 1,2 This state of reversible cell cycle arrest, known as quiescence, is common and can be seen in stem cells, eggs and spores. Some quiescent cells are surprisingly hardy: they can survive long periods of nutrient starvation, cold temperatures and even desiccation. Entry into quiescence is often associated with dramatic changes in metabolism, defined as the uptake of nutrients and the use of these nutrients for the synthesis of macromolecules and energy. Indeed, proliferating and quiescent fibroblasts are expected to have very different metabolic requirements. While proliferating cells must devote much of their metabolic capacity to biosynthesis in order to create the material necessary to form a new cell, quiescent cells are relieved of this steep metabolic requirement. Many but not all quiescent cells respond by downregulating the synthesis of proteins *Correspondence to: Hilary Coller; Email: hcoller@princeton.edu Submitted: 02/22/12; Accepted: 02/27/12 http://dx.doi.org/10. 4161/cc.19879 Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. in some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the Pi3Kinase/TOr signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOr kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. in this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems. 2 The signals for quiescence vary for different types of cells. Bacteria and yeast can enter stationary phase, a condition in which they cease cell growth and proliferation, in response to depletion of the glucose in their culture medium or in response to deprivation for a specific nutrient. In mammals, the proliferative state of individual cells is regulated by a host of factors that include not only the presence or absence of nutrients, but also cues from proliferative signaling molecules such as mitogens and situational cues. Quiescent T lymphocytes respond to stimulation of their T-cell receptor with the approp...

show abstract

Section: Quiescence In Fibroblastsmentioning

confidence: 99%

Staying alive

et al. 2012

View full text Add to dashboard Cite

show abstract

“…52 Consistent with this, FOXO3a, mTOR and GSK3β, downstream targets of the PI3K/Akt pathway, have been shown to be crucial modulators of HSC metabolism and quiescence. 19,[53][54][55] Intriguingly, niche signals such as TGFβ, Wnts or OPN could act on HSC fate by blocking this activation process, which would manifest itself by LRC inhibition. 17,23,24 Our experiments also show that other factors affecting LRC had a direct effect on c-Kit (and Sca-1) distribution in the membrane.…”

Section: Discussionmentioning

confidence: 99%

“…The PI3K-Akt signaling axis as well as the downstream effectors mTOR and FOXO transcription factors seem to play an important role. [16][17][18][19] Furthermore, recent work has demonstrated the relevance of metabolic modulators, including Lkb1 [20][21][22] in the regulation of HSC quiescence. Interestingly, changes in the distribution of lipid rafts, cell membrane microdomains enriched in cholesterol and…”

Section: Introductionmentioning

confidence: 99%

Identification of in vitro HSC fate regulators by differential lipid raft clustering

et al. 2012

View full text Add to dashboard Cite

“…125 Similarly, TSC1-mediated inhibition of the MTOR pathway, which contributes to HSC quiescence by repressing mitochondrial biogenesis and ROS production, also promotes autophagy. 49,50,[126][127][128][129] Given the tight regulation of mitochondrial content and activity in the maintenance of HSCs, the role of autophagy in mitochondrial turnover, and the coordinated regulation of mitochondrial function and autophagy, it is tempting to speculate that the defect in HSC/HPC function in autophagy-defective mice reflects a defect in mitochondrial clearance. Alternatively, autophagy may contribute to HSC maintenance by recycling key metabolites critical for survival of HSCs in the stem cell niche.…”

Section: Autophagy and Hscsmentioning

confidence: 99%

“…The HSCs derived from these TSC1-altered mice also have more mitochondria and higher ROS levels than do their wild-type counterparts. 49,50 ROS levels modulate attachment and mobility of HSCs, favoring exit of HSCs from the bone marrow niche. 51,52 Although low levels of ROS favor properties of stemness such as quiescence, higher self-renewal potential, maintenance of migratory potential and expansion of primitive and active HSCs in G 0 /G 1 phase, and appropriate amounts of ROS production are required for normal hematopoiesis, excessive ROS levels lead to significant HSC exhaustion, premature senescence, and divergence from stemness attributes, leading to a loss of stem cell function, inhibition of terminal differentiation of HSCs into various lineages, and apoptosis.…”

mentioning

confidence: 99%