While once considered a distinct cellular state, it is becoming clear that pluripotency is in fact a continuum of cellular states, all capable of selfrenewal and differentiation, yet. Embryonic stem es cell differentiation is a nonpathological cell system, in which proline metabolism was suggested to play a role. This has lead to an emerging paradigm, that mitochondrial oxidative metabolism is not just an indicator of the undifferentiated state of stem cells, but may also regulate the pluripotency and selfrenewal of stem cells. Glutamine regulates cardiac progenitor cell metabolism and proliferation. Plasticity in energy metabolism allows stem cells to match the divergent demands of selfrenewal and lineage specification. The function of hif1, a master regulator of metabolism, is in part modulated by cited2. Pluripotent stem cells possess a very specific metabolic profile that likely reflects. Review article controlling redox status for stem cell. Highthroughput screening assay for the identification of compounds regulating selfrenewal and differentiation in human embryonic stem cells. Malignant cells seem to hijack this metabolic switch, providing proproliferative metabolic conditions usually present upon stem cell activation. Metabolic regulation is crucial for maintaining stem cell homeostasis and cell differentiation 1,2,3,4,5,6,7,8. Metabolic regulation in pluripotent stem cells during. Metabolic inputs regulate epigenetics and cell signaling to promote changes in cell fate. Hence, it is becoming clear that physiological levels of ros play a role of secondary messengers in the regulation of stem cell fate.
Moreover, the maintenance of high glycolysis levels by hk2 and pkm2 overexpression hampers differentiation and preserves the pluripotency of escs in the absence of leukemia inhibitory factor. Understanding how the endoderm originates from es cells is the first step to generate specific cell types for therapeutic purposes. In this study, we identified ahcy, an important enzyme involved in the methionine metabolism, as a key player in the maintenance of stem cell identity. Studying proline metabolism in es cell differentiation will provide useful information about the metabolic control of cell programming and will identify potential targets for future research in cancers. Metabolic remodeling during the loss and acquisition of pluripotency. Beyond a role in energetic support, new evidence implicates nutrientresponsive metabolites as mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. Usp9x deubiquitinase couples the pluripotency network and cell metabolism to regulate. Metabolic regulation of dendritic cell differentiation. Glutamine metabolism regulates the pluripotency transcription factor oct4 article pdf available in cell reports 162. Oglcnacylation regulates the methionine cycle to promote. Both embryonic stem cells escs and adult stem cells ascs are.
Metabolically characterizing dynamic pluripotent stem cell states, as well as their derivatives, provides unprecedented insights into the metabolic pathways utilized by embryonic cells and, in conjunction with genetic and epigenetic studies, paints a more accurate and complete picture of the molecular landscape of early mammalian development. Pdf glutamine metabolism regulates the pluripotency. To study the earliest metabolic changes during the first steps of differentiation, we cultured i3 and i4 human embryonic stem cells hescs in suspension figure 1a amit et al. Metabolism is central to embryonic stem cell esc pluripotency and. Recent studies have demonstrated that psc and differentiated cells show altered.
Manipulation of pluripotent stem cell metabolism for clinical. Metabolic shift in densitydependent stem cell differentiation. Usp9x deubiquitinase couples the pluripotency network and. During embryonic development, pluripotent stem cells exist mostly in a hypoxic environment and are associated with the preference for glycolysis over oxidative phosphorylation oxphos 2, 9.
By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is regulated during. A common theme is that quiescent adult stem cells in hypoxic niches tend to prefer glycolysis and fatty acid oxidation. The significance of altered nutrient availability, particularly oxygen, and metabolic pathway activity has been highlighted by extensive studies of their impact on preimplantation embryo. Metabolic differentiation in the embryonic retina nature. Glycolysis produces metabolic intermediates that feed into the folate and one carbon metabolism cycle to produce s. Energy metabolism in human pluripotent stem cells and their. Human pluripotent stem cells hpscs are uniquely dependent on aerobic glycolysis to generate atp. Next, we focus on the effects of metabolism on regulating the balance. On the basis of the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells while monitoring the. Although limited, increasing numbers of studies are now revealing the importance of metabolic pathways involved in the modulation of dc development and. Moreover, metabolic intermediates of cellular metabolism regulate epigenetic mechanisms. Efforts to produce endodermal cell derivatives, including lung, liver and pancreas, have been met with modest success. Metabolic oxidation regulates embryonic stem cell differentiation article pdf available in nature chemical biology 66. With early differentiation, hpsc proliferation slows, energy metabolism decreases, and ucp2 is repressed, resulting in decreased glycolysis and maintained or increased mitochondrial glucose oxidation.
Neuronal differentiation is defined as the differentiation of embryonic stem cells into cells with i. By comparing the metabolism of pluripotent stem cells and cancer cells, we hope to illuminate common metabolic strategies as well as distinct metabolic features that. Flexibility in metabolic pathway utilization maintains a balance of anabolic processes to support synthesis of cellular building blocks, and catabolic processes to ensure adequate bioenergetic resources. Interplay between metabolites and the epigenome in regulating. Pluripotent stem cells pscs, including embryonic stem cells escs and induced pluripotent stem cells ipscs, have an unlimited capacity for selfrenewal and can differentiate into every cell type in our bodies, which holds significant promise for applications in regenerative medicine. As part of the identified signature, escs were found to contain a higher proportion of unsaturated metabolites, whereas differentiated cells contained higher. This is one example to make use of mpsc metabolism for differentiation. Controlling redox status for stem cell survival, expansion. Pluripotent stem cells pscs are powerful cellular tools that can generate all the different cell types of the body, and thus overcome the often limited access to human disease tissues. The levels of hk2 and pkm2 during dox treatment were determined by western blot. Cited2, a transcriptional modulator protein, regulates. Redox and metabolic regulator of stem cell state and. It has been assumed, based largely on morphologic evidence, that human pluripotent stem cells hpscs contain underdeveloped.
The overexpression of hk2 and pkm2 sustains high levels of glycolysis during embryonic stem cell esc differentiation. There is now a growing evidence that cell fate determination from stem cells implies a finetuned regulation of their energy balance and metabolic status. Interplay between metabolites and the epigenome in. It will be interesting to characterize the metabolic state of these stem cells to determine whether the relative dependence on. They also appear to influence stem cell function by regulating signal transduction, epigenetic marks and oxidative stress. Stem cell metabolism represents a combination and balance of the intrinsic metabolic needs and extrinsic metabolic constraints. Multiplatform nmr study of pluripotent stem cells unveils. Pluripotent stem cells pscs, including embryonic stem cells escs and induced pscs ipscs, are promising tools for regenerative medicine and important resources for studying epigenetic and metabolic changes during the transition between cell hierarchies 15. Fatty acid oxidation promotes reprogramming by enhancing. Stem cell metabolism in tissue development and aging.
Overexpression of hk2 and pkm2 sustains high glycolytic flux during embryonic stem cell differentiation. Stem cells can shift their metabolic substrate utilization, between glycolysis and mitochondrial oxidative metabolism, during specification andor differentiation, as well as in order to. Moreover, the metabolic shift observed during stem cell commitment leads to the increased levels of ros which are intrinsically linked with the differentiation stage of stem cells. Esc transition through different states of pluripotency in response to growth factor signals and environmental cues before becoming terminally differentiated. Revealing the metabolic characteristics of human embryonic stem. Metabolism is central to embryonic stem cell esc pluripotency and differentiation, with distinct profiles apparent under different nutrient milieu, and conditions that maintain alternate cell states. Feb 14, 2012 read ucp2 regulates energy metabolism and differentiation potential of human pluripotent stem cells, the embo journal on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. To our knowledge, cited2 is the first pro differentiation gene whose deletion affects glucose oxidation and in turn esc differentiation. Metabolic oxidation regulates embryonic stem cell differentiation. Pdf metabolic oxidation regulates embryonic stem cell. The role of nrf2 in regulating stem cell proliferation, differentiation, and programing stages depends upon the stem cell class esc, ipsc, hsc, msc, esc, nsc, epc, isc, etc.
Using msbased metabolomics, we show that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. A reduction in atp demand and mitochondrial activity with neural differentiation of human embryonic stem cells. Pdf embryonic stem cells esc have the unique ability to differentiate into all three germ cell layers. We also discuss the role of stemness factors in governing stem cell metabolism, and examine the role of stem cell metabolism during aging using insights gleaned from invertebrate. However, the importance of oxidative phosphorylation oxphos has not been elucidated. Hypoxia is a potent suppressor of mitochondrial oxidation and appears to promote stemness in adult and embryonic stem cells. Metabolic regulation of stem cell function burgess 2014. During such development, epigenetic alterations drive cell. Dec 19, 20 currently, common approaches to manipulating stem cell fate include genetic modification, by over.
Deletion of cited2 in mescs results in impaired mitochondria morphology, reduced glucose oxidation, increased glycolysis, and defective mesc differentiation. Recently, it has been demonstrated that inhibition of myc or. Most studies on the control of cell fate decisions address the contributions of changes in transcriptional programming, epigenetic modifications, and biochemical differentiation cues. What are the lineagespecific pathways and mechanisms by which nrf2 regulates stem cell redox and metabolic homeostasis and stem cell integrity and fate determination.
Apr 08, 2015 stem cell basics last modified on april 08, 2015 about this document this primer on stem cells is intended for anyone who wishes to learn more about the biological properties of stem cells, the important questions about stem cells that are the focus of scientific research, and the potential use of stem cells in research and in treating disease. Tsogtbaatar e, landin c, minterdykhouse k and folmes cdl 2020 energy metabolism regulates stem cell pluripotency. Here, we demonstrated, by a multiomic strategy, that the deubiquitinase usp9x regulates the developmental potential of esc, and their. Ucp2 regulates energy metabolism and differentiation. Differential alternative polyadenylation landscapes. Metabolic oxidation controls the hepatic stem cells. Neuronal differentiation is defined as the differentiation of embryonic stem cells into cells with i neuron morphology, namely a small round cell body consisting of multiple processes, and ii clear neuronspecific class iii. Cited2 coordinates glucose metabolism to regulate mesc differentiation. Mar, 2019 as metabolism is the essential process in all cell types, the effects of metabolic pathways on immune cell differentiation and functions have recently attracted great attention 2932.
Metabolic oxidation controls the hepatic stem cells hpscs. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is regulated during differentiation. Core pluripotency factors directly regulate metabolism in. Yanes o1, clark j, wong dm, patti gj, sanchezruiz a, benton hp, trauger sa, desponts c, ding s, siuzdak g. Detailed amino acid profiling has revealed that glutamine is indispensable for the survival of hpscs.
Metabolic control of stemness and differentiation hindawi. Yanes o, clark j, wong dm, patti gj, sanchezruiz a, benton hp, et al. Frontiers stem cell metabolism in cancer and healthy. Pluripotent stem cells pscs are characterized by their unique capacity for both unlimited selfrenewal and their potential to differentiate to all cell lineages contained within the three primary germ layers. Embryonic stem cells esc have the unique ability to differentiate into all three germ cell layers. Nih public access diana m wong gary j patti antonio sanchez. Differential expression of glucose transporter isoforms during embryonic stem cell differentiation. Nih public access diana m wong gary j patti antonio. Cited2, a transcriptional modulator protein, regulates metabolism in murine embryonic stem cells article pdf available in journal of biological chemistry 2891 november 20 with 75 reads.
The salubrious effects of gln on cpcs appear to be due to generation of products of gln oxidation, as provision of cell permeable. Ahcy is dynamically modified by a single sugar nacetylglucosamine, which responds to environmental cues to regulate its activity, and further influences stem cell proliferation and differentiation. The role of cited2 in murine embryonic stem cell mesc glucose metabolism remains unknown. Neuronal differentiation is defined as the differentiation of embryonic stem cells into cells. Metabolic signatures of cancer cells and stem cells. Overall, our results suggest that the activation of oxidation is a metabolic signature of stemcell differentiation. Oct 20, 2017 vascular progenitor cells vpcs derived from embryonic stem cells escs are a valuable source for cell and tissuebased therapeutic strategies. Overall, hpscs contain active mitochondria and require ucp2 repression for full differentiation potential. Nonetheless their use may prove challenging as incomplete differentiation of these cells might lead to tumoregenicity. Metabolic oxidation regulates embryonic stem cell differentiation oscar yanes1, julie clark2, diana m wong1, gary j patti1, antonio sanchezruiz2, h paul benton1, sunia a trauger1, caroline. Embryonic stem es cells can differentiate in vitro into a variety of cell types. Understanding how cell fate decisions are regulated is a fundamental goal of developmental and stem cell biology.
Revisiting mitochondrial function and metabolism in. Metabolic plasticity in stem cell homeostasis and differentiation. Some of these adult stem cells cycle slowly, such as skin stem cells in the hair follicle, whereas some cycle rapidly, such as intestinal crypt stem cells. We compared two different lines of mouse embryonic stem cells mescs that have greater than 99% homogeneity 46c mesc and r1 mesc. Mitochondrial metabolism in hesc and hipsc differentiation. Modulation of the pentose phosphate pathway induces. In response to an activating signal such as physical trauma, satellite cells enter the cell cycle and undergo multiple rounds of proliferation, followed by differentiation, fusion, and maturation. Glutamine metabolism regulates the pluripotency of human embryonic stem cells hescs oct4 undergoes cysteine oxidation and degradation during glutamine withdrawal metabolic cues act in concert with growth factors to regulate stem cell differentiation glutamine withdrawal enhances the angiogenic capacity of escderived endothelial cells. Ectopic ucp2 expression perturbs this metabolic transition. Background human pluripotent stem cells have the ability to generate all cell types present in the adult organism, therefore harboring great potential for the in vitro study of differentiation and for the development of cell based therapies. Inhibition of glycolysis or acetylcoa led to differentiation of embryonic stem cells. Glutamine regulates cardiac progenitor cell metabolism and. This implicates mitochondria as the key player in esc differentiation and metabolic reprogramming, which may represent a unique way to modulate the fate of escs. Based on the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells.
Metabolic requirements are defined by the energetic demands of stem cell proliferation. Studies to date illustrate the importance of metabolism in the regulation of stem cell function and suggest complex cross. Inhibition of the eicosanoid signaling pathway promoted pluripotency and maintained levels of unsaturated fatty acids. Metabolic reprogramming as a novel regulator of skeletal. Ectopic ucp2 expression perturbs this metabolic transition and impairs hpsc differentiation.
Collectively, we report the cell type and cell statespecific apaomes of hscs and downstream progenitors and demonstrate that apamediated gls isoform switching is a key component of the metabolic. Increasing evidence highlights a pivotal role for metabolism in stem cell physiology. Expanding the arsenal of analytical tools for metabolic profiling of cell differentiation is therefore of importance. On the basis of the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells while monitoring the effects on differentiation. Metabolites offer an important unexplored complementary approach to understanding the pluripotency of stem cells. Ros generation and scavenging in stem cells stem cell physiology and metabolism are tightly regulated by oxidation reduction events that mainly occur during respiratory chain.
224 941 1542 318 1330 434 825 646 1638 728 268 105 437 104 219 660 565 550 270 1536 983 1110 609 1292 686 372 244 165 1358 1052 1196 297 1275 113 1386 573 291 872 667 383 319 438 435