Hypoxic metabolism in human hematopoietic stem cells

Kocabaş, Fatih; Xie, Li; Xie, Jingjing; Yu, Zhuang; DeBerardinis, Ralph J.; Kimura, Wataru; Thet, Suwannee; Elshamy, Ahmed F.; Abouellail, Hesham; Muralidhar, Shalini; Liu, Xiaoye; Chen, Chiqi; Sadek, Hesham A.; Zhang, Cheng Cheng; Zheng, Junke

doi:10.1186/s13578-015-0020-3

Cited by 73 publications

(95 citation statements)

References 55 publications

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“…Recently, metabolic regulation of stem/progenitor cell with inherent capacity for self-renewal is attracting more and more interest (Simsek et al, 2010;Harjes et al, 2012;Kocabas et al, 2015). Previous reports show that adult hematopoietic stem cells are challenged by low oxygen milieu when reside in the bone marrow.…”

Section: Discussionmentioning

confidence: 99%

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

Song

Yang

Qiu

et al. 2017

Cell Biology International

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The objective of the research was to investigate the function of endothelial progenitor cells (EPCs) in the conditions of high glucose and lipids, which has been widely used to mimic the metabolic disorder that occurs in type 2 diabetic mellitus, and further to verify the role of PGC-1α and SIRT1, cellular energy metabolism regulators, in the process of senescence of EPCs with these combined stimuli. Circulating EPCs were incubated in absence or presence of high glucose (25 mM), FFA (200 µM) or both. EPCs senescence was assessed by β-galactosidase staining, EPCs telomerase activity was measured by telomeric repeat ampli-fication protocol assay, in vitro angiogenesis assay and MTT assays were performed to assess angiogenesis and proliferation ability of EPCs. The results showed that combined stimuli inhibited EPCs reendothelialization ability in vitro, accelerated EPCs senescence and decreased the telomerase activity. Meanwhile, with combined stimuli, the expression of PGC-1α increased whereas SIRT1 expression decreased in EPCs accompanied by activation of P53/P21 signaling pathway. Conversely, transfection of EPCs with PGC-1α-siRNA rescued EPCs premature senescence and up-regulated SIRT1 and decreased P53/P21 expression, correlating closely with the down-regulation of PGC-1α itself. In addition, the combined stimuli induced up-regulation of PGC-1α expression was partly mediated by ROS and P38 signaling pathway. Overall, the data presented here identify PGC-1α as a potent negative regulator of EPCs' senescence under combined stimuli, which is partly mediated by SIRT1/P53/P21 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

Song

Yang

Qiu

et al. 2017

Cell Biology International

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“…Lactate generation was measured using the Seahorse XF96 extracellular flux analyzer as previously described, with minor modifications [49]. Briefly, three replicate wells of 3 × 10 5 WT or ChREBP-null AML cells per well were seeded in 96-well XF96 plates coated with BD Cell-Tak (BD Biosciences) in unbuffered DMEM and incubated at 37°C for pH stabilization.…”

Section: Methodsmentioning

confidence: 99%

ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways

Zeng

Chen

et al. 2016

Oncotarget

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Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment.

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“…For example, BM-MSCs cultured in HG medium exhibited senescence and genetic instability by upregulation of autophagy and oxidative stress (Chang et al, 2015). In addition, hyperglycemia impaired the proliferation and function of endogenous stem and somatic cells such as MSCs, hematopoietic stem cells and Müller cells (Kim et al., 2015; Kocabas et al ., 2015; Manea et al ., 2015; Hadarits et al, 2016; Qiu et al ., 2016). Thus, we assumed that the glucose concentration in the culture medium may affect the expression levels of ion channels in PVCs and found increased levels of BK Ca β 3a , BK Ca β 4 , K v 1.3, K v 1.6, and K v 6.1 transcripts in HG-treated PVCs compared to those of LG-treated PVCs.…”

Section: Discussionmentioning

confidence: 99%

Expression of Ion Channels in Perivascular Stem Cells derived from Human Umbilical Cords

2017

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Potassium channels, the largest group of pore proteins, selectively regulate the flow of potassium (K+) ions across cell membranes. The activity and expression of K+ channels are critical for the maintenance of normal functions in vessels and neurons, and for the regulation of cell differentiation and maturation. However, their role and expression in stem cells have been poorly understood. In this study, we isolated perivascular stem cells (PVCs) from human umbilical cords and investigated the expression patterns of big-conductance Ca2+-activated K+ (BKCa) and voltage-dependent K+ (Kv) channels using the reverse transcription polymerase chain reaction. We also examined the effect of high glucose (HG, 25 mM) on expression levels of BKCa and Kv channels in PVCs. KCa1.1, KCaβ3, Kv1.3, Kv3.2, and Kv6.1 were detected in undifferentiated PVCs. In addition, HG treatment increased the amounts of BKCaβ3a, BKCaβ4, Kv1.3, Kv1.6, and Kv6.1 transcripts. These results suggested that ion channels may have important functions in the growth and differentiation of PVCs, which could be influenced by HG exposure.

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Hypoxic metabolism in human hematopoietic stem cells

Cited by 73 publications

References 55 publications

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways

Expression of Ion Channels in Perivascular Stem Cells derived from Human Umbilical Cords

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