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Quiescent fibroblasts exhibit high metabolic activity.
PLoS Biol. 2010; 8(10):e1000514
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18 Nov 2010
Lucio Comai
F1000 Cell Biology
Keck School of Medicine, University of Southern California,
Los Angeles, CA, USA.
F1000 Cell Biology
Keck School of Medicine, University of Southern California,
Los Angeles, CA, USA.
DOI: 10.3410/f.6131956.6168054
The concept that cell quiescence is invariably accompanied by diminished metabolic rates is put into question by this paper, which demonstrates high rates of glycolysis and pentose phosphate pathways in quiescent fibroblasts.
The authors utilized contact-inhibition and serum starvation as two conditions...Continue reading
The authors utilized contact-inhibition and serum starvation as two conditions...Continue reading
The concept that cell quiescence is invariably accompanied by diminished metabolic rates is put into question by this paper, which demonstrates high rates of glycolysis and pentose phosphate pathways in quiescent fibroblasts.
The authors utilized contact-inhibition and serum starvation as two conditions for inducing cellular quiescence and determined that glycolytic rates were essentially unchanged when compared to actively proliferating cells. These data indicate that, unlike other cell systems, e.g. lymphocytes, which undergo a major metabolic down shift, fibroblasts maintain a high level of metabolism upon entering quiescence. Now additional studies are needed to determine if the high metabolic rates are required to ensure the presence of the healthy milieu of cellular components necessary for cell survival and whether this process is affected by aging.
The authors utilized contact-inhibition and serum starvation as two conditions for inducing cellular quiescence and determined that glycolytic rates were essentially unchanged when compared to actively proliferating cells. These data indicate that, unlike other cell systems, e.g. lymphocytes, which undergo a major metabolic down shift, fibroblasts maintain a high level of metabolism upon entering quiescence. Now additional studies are needed to determine if the high metabolic rates are required to ensure the presence of the healthy milieu of cellular components necessary for cell survival and whether this process is affected by aging.
Disclosures
None declared
Add Comment
Comai L: F1000Prime Recommendation of [Lemons JM et al., PLoS Biol 2010, 8(10):e1000514]. In F1000Prime, 18 Nov 2010; DOI: 10.3410/f.6131956.6168054. F1000Prime.com/6131956#eval6168054
18 Nov 2010
DOI: 10.3410/f.6131956.6311054
This article reports the remarkable metabolic activity of mammalian quiescent fibroblasts that were previously considered to be metabolically much more dormant. Being of general interest, it should also be appreciated by those studying intracellular pathogens and using fibroblasts as convenient host cells.
The...Continue reading
The...Continue reading
This article reports the remarkable metabolic activity of mammalian quiescent fibroblasts that were previously considered to be metabolically much more dormant. Being of general interest, it should also be appreciated by those studying intracellular pathogens and using fibroblasts as convenient host cells.
The general concept that proliferating and quiescent cells have very different metabolic needs is easy to understand (no need to provide metabolites to build a new cell) but may require a closer look for different cell types in the future. Lemons and colleagues show in their comprehensive study that contact-inhibited human primary skin fibroblasts utilize glucose in all branches of central carbon metabolism at similar rates compared to their proliferating cousins. Although some aspects of their metabolism differ in detail (e.g. diversion of glucose to the pentose phosphate pathway, anaplerotic flux from pyruvate to oxaloacetate through pyruvate carboxylase and enhanced macromolecular degradation rates in quiescent fibroblasts) the overall metabolic rate is remarkably similar and seems to equip the non-proliferating cells with a surplus of NADPH that could be used in the defense against oxidative stress via GSH (glutathione) and thioredoxin production.
Since quiescent (contact-inhibited) fibroblasts are used in the lab as convenient host cells for a number of intracellular pathogens (e.g. Toxoplasma gondii), and many aspects of host-pathogen interactions depend also on metabolic cross-talk between both entities, these findings will also be of relevance to these systems.
The general concept that proliferating and quiescent cells have very different metabolic needs is easy to understand (no need to provide metabolites to build a new cell) but may require a closer look for different cell types in the future. Lemons and colleagues show in their comprehensive study that contact-inhibited human primary skin fibroblasts utilize glucose in all branches of central carbon metabolism at similar rates compared to their proliferating cousins. Although some aspects of their metabolism differ in detail (e.g. diversion of glucose to the pentose phosphate pathway, anaplerotic flux from pyruvate to oxaloacetate through pyruvate carboxylase and enhanced macromolecular degradation rates in quiescent fibroblasts) the overall metabolic rate is remarkably similar and seems to equip the non-proliferating cells with a surplus of NADPH that could be used in the defense against oxidative stress via GSH (glutathione) and thioredoxin production.
Since quiescent (contact-inhibited) fibroblasts are used in the lab as convenient host cells for a number of intracellular pathogens (e.g. Toxoplasma gondii), and many aspects of host-pathogen interactions depend also on metabolic cross-talk between both entities, these findings will also be of relevance to these systems.
Disclosures
None declared
Seeber F: F1000Prime Recommendation of [Lemons JM et al., PLoS Biol 2010, 8(10):e1000514]. In F1000Prime, 18 Nov 2010; DOI: 10.3410/f.6131956.6311054. F1000Prime.com/6131956#eval6311054
15 Dec 2010
Technical Advance
DOI: 10.3410/f.6131956.7173054
I found this article interesting because the authors show, for the first time, that quiescent fibroblasts are metabolically very active. This is a novel finding, because the dogma has been that these cells shut down most metabolic activities.
The authors used "metabolomics" to compare primary human fibroblasts...Continue reading
The authors used "metabolomics" to compare primary human fibroblasts...Continue reading
I found this article interesting because the authors show, for the first time, that quiescent fibroblasts are metabolically very active. This is a novel finding, because the dogma has been that these cells shut down most metabolic activities.
The authors used "metabolomics" to compare primary human fibroblasts that were arrested in their growth, either due to contact inhibition, serum withdrawal, or both, with proliferating cells. The surprising finding is that the quiescent fibroblasts are highly metabolically active, converting the glucose to the pentose phosphate pathway to generate NADPH. This is in contrast to earlier reports that quiescent lymphocytes have extremely low metabolic activity {1-5}. It is possible that the state of quiescence differs in various cell types, but it is more likely that the techniques used in the current paper are much more sensitive than in previous analyses. The main point that is clearly made in the current paper is that quiescence is an active, but not a default, state that requires high metabolic activity.
The authors used "metabolomics" to compare primary human fibroblasts that were arrested in their growth, either due to contact inhibition, serum withdrawal, or both, with proliferating cells. The surprising finding is that the quiescent fibroblasts are highly metabolically active, converting the glucose to the pentose phosphate pathway to generate NADPH. This is in contrast to earlier reports that quiescent lymphocytes have extremely low metabolic activity {1-5}. It is possible that the state of quiescence differs in various cell types, but it is more likely that the techniques used in the current paper are much more sensitive than in previous analyses. The main point that is clearly made in the current paper is that quiescence is an active, but not a default, state that requires high metabolic activity.
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Disclosures
None declared
Huber B: F1000Prime Recommendation of [Lemons JM et al., PLoS Biol 2010, 8(10):e1000514]. In F1000Prime, 15 Dec 2010; DOI: 10.3410/f.6131956.7173054. F1000Prime.com/6131956#eval7173054
F1000Prime Recommendations, Dissents and Comments for [Lemons JM et al., PLoS Biol 2010, 8(10):e1000514]. In F1000Prime, 19 May 2013; F1000Prime.com/6131956
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Comment by:
Richard Grant,
F1000
11 Apr 2011, 5:36 PM
11 Apr 2011, 5:36 PM
Read our 'Hidden Jewel' article in The Scientist, with further comment from Lucio Comai and Hilary Coller: http://www.the-scientist.com/article/display/57934/
Disclosures:
None declared.
Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a "backwards" flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole.
DOI: 10.1371/journal.pbio.1000514
PMID: 21049082
