Hypoxia Signaling Pathway in Stem Cell Regulation: Good and Evil

Huang, Xinxin; Trinh, Thao; Aljoufi, Arafat; Broxmeyer, Hal E.

doi:10.1007/s40778-018-0127-7

Cited by 60 publications

(57 citation statements)

References 113 publications

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“…Hypoxia promotes cell growth and migration, and it helps maintain cell stemness [8,9]. The effects of hypoxia are primarily mediated by hypoxia-inducible factors (HIFs) [10], which are DNA-binding transcriptional factors and bind to hypoxia-regulated elements (HREs) in the promoter and enhancer of target genes [10]. In normal oxygen condition, HIF-1α nuclear translocation is consistently diminished by prolyl hydroxylase 2-(PHD2-) mediated hydroxylation [11].…”

Section: Introductionmentioning

confidence: 99%

Succinate Supplement Elicited “Pseudohypoxia” Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells

Mao

Yang

Zhao

et al. 2020

Stem Cells International

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Most mesenchymal stem cells reside in a niche of low oxygen tension. Iron-chelating agents such as CoCl2 and deferoxamine have been utilized to mimic hypoxia and promote cell growth. The purpose of the present study was to explore whether a supplement of succinate, a natural metabolite of the tricarboxylic acid (TCA) cycle, can mimic hypoxia condition to promote human periodontal ligament cells (hPDLCs). Culturing hPDLCs in hypoxia condition promoted cell proliferation, migration, and osteogenic differentiation; moreover, hypoxia shifted cell metabolism from oxidative phosphorylation to glycolysis with accumulation of succinate in the cytosol and its release into culture supernatants. The succinate supplement enhanced hPDLC proliferation, migration, and osteogenesis with decreased succinate dehydrogenase (SDH) expression and activity, as well as increased hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), suggesting metabolic reprogramming from oxidative phosphorylation to glycolysis in a normal oxygen condition. The succinate supplement in cell cultures promoted intracellular succinate accumulation while stabilizing hypoxia inducible factor-1α (HIF-1α), leading to a state of pseudohypoxia. Moreover, we demonstrate that hypoxia-induced proliferation was G-protein-coupled receptor 91- (GPR91-) dependent, while exogenous succinate-elicited proliferation involved the GPR91-dependent and GPR91-independent pathway. In conclusion, the succinate supplement altered cell metabolism in hPDLCs, induced a pseudohypoxia condition, and enhanced proliferation, migration, and osteogenesis of mesenchymal stem cells in vitro.

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Section: Introductionmentioning

confidence: 99%

Succinate Supplement Elicited “Pseudohypoxia” Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells

Mao

Yang

Zhao

et al. 2020

Stem Cells International

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“…Hypoxia conditions have been frequently employed in stem cell biology and control stem cell functions through the HIF signaling pathway. 150) In a study involving direct reprogramming, these conditions were also used to accelerate conversion. 151),152) On the other hand, micro-or nano-imprinted patterns, e.g., microgrooves, of cultured cell substrates are known as enhancers of reprogramming in biomaterials science.…”

Section: Partial Reprogramming With Specific Culture Conditionsmentioning

confidence: 99%

Direct cell-fate conversion of somatic cells: Toward regenerative medicine and industries

Horisawa

Suzuki

2020

Proc. Jpn. Acad., Ser. B

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Cells of multicellular organisms have diverse characteristics despite having the same genetic identity. The distinctive phenotype of each cell is determined by molecular mechanisms such as epigenetic changes that occur throughout the lifetime of an individual. Recently, technologies that enable modification of the fate of somatic cells have been developed, and the number of studies using these technologies has increased drastically in the last decade. Various cell types, including neuronal cells, cardiomyocytes, and hepatocytes, have been generated using these technologies. Although most direct reprogramming methods employ forced transduction of a defined sets of transcription factors to reprogram cells in a manner similar to induced pluripotent cell technology, many other strategies, such as methods utilizing chemical compounds and microRNAs to change the fate of somatic cells, have also been developed. In this review, we summarize transcription factor-based reprogramming and various other reprogramming methods. Additionally, we describe the various industrial applications of direct reprogramming technologies.

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“…Unexpectedly however, we observed a reduction in SOCS3 protein level by DENV infection for which either mechanism or implication with respect to viral life cycle is still unclear. In the BM, pluripotent hematopoietic stem cells (HSCs) reside in a relatively hypoxic area while during differentiation megakaryocytes relocate to more oxygen-rich region near blood vessels from where platelets can be shed into the vascular circulation (102). ROS serves a critical role in megakaryocyte formation since a low level of these signaling molecules in differentiating HSCs disfavor generation of (Megakaryocyte-Erythrocyte progenitors) MEP and in favor of (Granulocyte-Monocyte progenitors) GMP (103).…”

Section: Pma-induced Transcriptome Changes Are Reversed By Denv Infecmentioning

confidence: 99%

Megakaryopoiesis in Dengue virus infected K562 cell promotes viral replication which inhibits endomitosis and accumulation of ROS associated with differentiation

Kaur

Rawat

Sood

et al. 2020

Preprint

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AbstractIn the human host blood Monocytes and bone marrow Megakaryocytes are implicated as major sites supporting high replication. The human K562 cell line supports DENV replication and represent Megakaryocyte-Erythrocyte progenitors (MEP), replicating features of in vivo Megakaryopoiesis upon stimulation with Phorbol esters. In this article, we report results that indicate the mutual influence of Megakaryopoiesis and DENV replication on each other, through comparison of PMA-induced differentiation of either mock-infected or DENV-infected K562 cells. We present data showing PMA-induced differentiation to drastically increase DENV replication and a concomitant augmented secretion of infectious virus. Although the mechanism is not clear yet, we show that it is not through an increased uptake of virus by differentiated cells. On the other hand, DENV replication in cells undergoing PMA-induced differentiation, interferes with major differentiation markers of Megakaryopoiesis including activation of ERK1/2 MAP Kinase, endomitosis and surface expression of platelet-specific proteins without any drastic effect on cell death. Among signaling intermediaries of the JAK-STAT pathway, we observed infection associated degradation of SOC3 protein similar to earlier observations with STAT2. DENV infection leads to accumulation of Reactive-oxygen species (ROS) in different cells including K562. PMA-induced differentiation of uninfected K562 cells also leads to intracellular ROS accumulation. Interestingly, we observed ROS accumulation to be suppressed by concomitant DENV replication in K562 cells undergoing PMA-induced differentiation. This is the first report of a model system where DENV replication suppresses intracellular ROS accumulation. The implications of these results for Megakaryopoiesis and viral replication would be discussed.

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Hypoxia Signaling Pathway in Stem Cell Regulation: Good and Evil

Cited by 60 publications

References 113 publications

Succinate Supplement Elicited “Pseudohypoxia” Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells

Succinate Supplement Elicited “Pseudohypoxia” Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells

Direct cell-fate conversion of somatic cells: Toward regenerative medicine and industries

Megakaryopoiesis in Dengue virus infected K562 cell promotes viral replication which inhibits endomitosis and accumulation of ROS associated with differentiation

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