A High Glycolytic Flux Supports the Proliferative Potential of Murine Embryonic Stem Cells

Abstract

Embryonic stem (ES) cells are immortal and present the ability to self-renew while retaining their ability to differentiate. In contrast, most primary cells possess a limited proliferative potential, and when this is exhausted, undergo an irreversible growth arrest termed senescence. In primary cells, senescence can be also triggered by a variety of stress to which ES cells are highly refractory. Here the authors report that the proliferative capacity of murine ES cells closely correlates with high activity of different glycolytic enzymes, elevated glycolytic flux, and low mitochondrial oxygen consumption. The direct relation between glycolytic flux and the ability of ES cells to proliferate is further remarked in experiments where glycolysis or ES cell self-renewal was specifically inhibited. It was previously reported that the upregulation of glycolysis in primary cells results in life span extension. The authors hypothesize that the naturally high glycolytic flux observed in murine ES cells can be responsible for their unlimited proliferative potential.

Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205

“…[106][107][108][109][110][111][112] Conversely, the glycolytic flux declines during the establishment of senescence both in MEFs and HDFs, whereas upregulation of glycolysis in primary cells results in lifespan extension. [98][99][100] These data, altogether, support the hypothesis that enhanced glycolysis is a fundamental mechanism that, by endowing metabolic refractoriness to a variety of stress inducing senescence including oxidative stress, actively maintains the unlimited proliferative potential of "immortal" stem cells. [106][107][108][109][110][111][112] Because the direct relation between glycolytic flux and the ability of stem cells to proliferate has been remarked upon in earlier studies, where glycolysis or stem cells self-renewal was specifically inhibited, 99 our current findings revealing for the first time metformin's ability to negatively impact the proliferative potential of iPSCs strongly suggest that the metformin-imposed cell bioenergetics efficiently bypass stemness-related resistance to stress.…”

“…[98][99][100] These data, altogether, support the hypothesis that enhanced glycolysis is a fundamental mechanism that, by endowing metabolic refractoriness to a variety of stress inducing senescence including oxidative stress, actively maintains the unlimited proliferative potential of "immortal" stem cells. [106][107][108][109][110][111][112] Because the direct relation between glycolytic flux and the ability of stem cells to proliferate has been remarked upon in earlier studies, where glycolysis or stem cells self-renewal was specifically inhibited, 99 our current findings revealing for the first time metformin's ability to negatively impact the proliferative potential of iPSCs strongly suggest that the metformin-imposed cell bioenergetics efficiently bypass stemness-related resistance to stress. If cells' ability to reprogram their ATP-generating energy metabolism by replacing the mitochondrial oxidative phosphorylation that operates in most normal, non-proliferative tissues to a Warburg-like glycolytic metabolism that more efficiently supports the large-scale biosynthetic programs required for continuous cell growth and proliferation is necessary and sufficient to enable indefinite proliferation, it is reasonable to suggest that metformin treatment circumvent the SIS-resistant phenotype of stem cells by imposing a normalized metabolic flow away from the required pro-immortalizing glycolysis that fuels induction of stemness and pluripotency.…”

“…Changes in the carbohydrate metabolism and, in particular, in the regulation of glycolytic energy production also contribute to regulate SIS in fibroblasts. [98][99][100] The fact that metformin treatment sensitizes MEFs to the pro-senescent effects induced by the ROS-generating DNA damaging agent doxorubicin may reflect a dual growth-suppressive nature of metformin involving resetting of cellular bioenergetics and metabolic activation of a DNA damage response (DDR) attributable to enhanced levels of ROS. Metformin, like doxorubicin, induces autophosphorylation of the DNA damage sensor Ataxia-Telangiectasia mutated (ATM) kinase and the ATM-dependent phosphorylation of multiple downstream effectors within the DNA damage response pathway, including the checkpoint kinase Chk2.…”

Cell signalling pathways underlying induced pluripotent stem cell reprogramming

“…phorylation to anaerobic glycolysis, pre-iPS cells assume an ES cell-like phenotype [68] . ES cells are likely to have developed this form of metabolism as an adaptation to the hypoxic in vivo environment of the early embryo [69] .…”

The mitochondrial H+-ATP synthase and the lipogenic switch

“…The previously unrecognized ability of iPS cells to accumulate significant amounts of neutral lipid depots in terms of the molecular pathways they invoke. [32][33][34][73][74][75][76][77][78][79][80][81][82][83][84] Here, we tested the hypothesis that the H + -ATPase synthase-geared metabolism switch, 15 a mitochondria-mediated energy adaptation that is sufficient to promote the acquisition of the Warburg phenotype, is also employed during somatic reprogramming to limit the bioenergetic activity of mitochondria and mediates the shift of iPS cells to enhanced aerobic glycolysis. As in the majority of cancer cells, in which the Warburg phenotype can be acquired without any genetic alteration, the peculiar energy metabolism of iPS cells is a "reversible trait" that is rapidly modulated in response to changes in AMPK activation status.…”