A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism

Mei, Yuqin; Pan, Zongfu; Chen, Wen-teng; Xu, Minhua; Zhu, Danyan; Yu, Yongping; Lou, Yijia

doi:10.1371/journal.pone.0157747

Cited by 12 publications

(9 citation statements)

References 47 publications

(67 reference statements)

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“…However, in-depth studies are needed to fully understand how flavone derivatives regulate astrocyte function and promote astrocytogenesis especially in NSC by PD98059, compound 2, and 3. Like our results, flavonoids have been known to regulate NSC fate [47,48]. It has been known that epigallocatechin-3-gallate induces proliferation and promotes neurogenesis of mouse cochlear NSCs [47].…”

Section: The 3 -Methoxy Group (Methoxy Group At R 2 Position) and Nonsupporting

confidence: 86%

Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

et al. 2019

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Neural stem cells (NSCs) differentiate into multiple cell types, including neurons, astrocytes, and oligodendrocytes, and provide an excellent platform to screen drugs against neurodegenerative diseases. Flavonoids exert a wide range of biological functions on several cell types and affect the fate of NSCs. In the present study, we investigated whether the structure-activity relationships of flavone derivatives influence NSC differentiation. As previously reported, we observed that PD98059 (2′-amino-3′-methoxy-flavone), compound 2 (3′-methoxy-flavone) induced astrocytogenesis. In the present study, we showed that compound 3 (2′-hydroxy-3′-methoxy-flavone), containing a 3′-methoxy group, and a non-bulky group at C2′ and C4′, induced astrocytogenesis through JAK-STAT3 signaling pathway. However, compound 1 and 7–12 without the methoxy group did not show such effects. Interestingly, the compounds 4 (2′,3′-dimethoxyflavone), 5 (2′-N-phenylacetamido-3′-methoxy-flavone), and 6 (3′,4′-dimethoxyflavone) containing 3′-methoxy could not promote astrocytic differentiation, suggesting that both the methoxy groups at C3′ and non-bulky group at C2′ and C4′ are required for the induction of astrocytogenesis. Notably, compound 6 promoted neuronal differentiation, whereas its 4′-demethoxylated analog, compound 2, repressed neurogenesis, suggesting an essential role of the methoxy group at C4′ in neurogenesis. These findings revealed that subtle structural changes of flavone derivatives have pronounced effects on NSC differentiation and can guide to design and develop novel flavone chemicals targeting NSCs fate regulation.

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Section: The 3 -Methoxy Group (Methoxy Group At R 2 Position) and Nonsupporting

confidence: 86%

Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

et al. 2019

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“…Several kinds of flavonoids are known to regulate cell adhesion, proliferation, and differentiation in stem cells [42][43][44]. To determine the role of flavonoid of PBMC-hiPSCs, we added one of the flavonoids with differential structures during the culturing process of the hiPSCs (Supplementary Figure S2).…”

Section: 2 -Dhf Treatment Promoted Proliferation and Suppressed Dissociation-induced Apoptosis Of Hipscsmentioning

confidence: 99%

3,2′-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells

Kim

Dayem

Gil

et al. 2020

JCM

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Efficient maintenance of the undifferentiated status of human pluripotent stem cells (hiPSCs) is crucial for producing cells with improved proliferation, survival and differentiation, which can be successfully used for stem cell research and therapy. Here, we generated iPSCs from healthy donor peripheral blood mononuclear cells (PBMCs) and analyzed the proliferation and differentiation capacities of the generated iPSCs using single cell NGS-based 24-chromosome aneuploidy screening and RNA sequencing. In addition, we screened various natural compounds for molecules that could enhance the proliferation and differentiation potential of hiPSCs. Among the tested compounds, 3,2′-dihydroxyflavone (3,2′-DHF) significantly increased cell proliferation and expression of naïve stemness markers and decreased the dissociation-induced apoptosis of hiPSCs. Of note, 3,2′-DHF-treated hiPSCs showed upregulation of intracellular glutathione (GSH) and an increase in the percentage of GSH-high cells in an analysis with a FreSHtracer system. Interestingly, culture of the 3,2′-DHF-treated hiPSCs in differentiation media enhanced their mesodermal differentiation and differentiation into CD34+ CD45+ hematopoietic progenitor cells (HPC) and natural killer cells (NK) cells. Taken together, our results demonstrate that the natural compound 3,2′-DHF can improve the proliferation and differentiation capacities of hiPSCs and increase the efficiency of HPC and NK cell production from hiPSCs.

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“…For example, PPARβ/δ controls on a transcriptional level the endothelial differentiation gene (Edg)-2 and PPARβ/δ agonist stimulation enhances the vasculogenic potential of endothelial progenitor cells (EPCs) [ 110 ]. Moreover, it has been shown that PPARβ/δ can promote osteoblast differentiation via Wnt signaling [ 30 ], in a keratinocyte fatty acid binding protein (K-FABP)-dependent manner keratinocyte differentiation [ 111 ], early adipocyte differentiation via PPARγ [ 112 , 113 ], late sebocyte differentiation [ 114 ], oligodendrocyte [ 115 , 116 ] and neural [ 117 ] differentiation, as well as p53- and SOX2-mediated differentiation of neuroblastoma cells [ 118 ]. Finally, the PPARβ/δ target gene FoxO1 plays an important role as negative regulator of skeletal muscle differentiation [ 119 , 120 ].…”

Section: Pparβ/δ Controls Basic Mechanisms Of Wound Healing and Rementioning

confidence: 99%

PPARβ/δ: Linking Metabolism to Regeneration

Magadum

Engel

2018

IJMS

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In contrast to the general belief that regeneration is a rare event, mainly occurring in simple organisms, the ability of regeneration is widely distributed in the animal kingdom. Yet, the efficiency and extent of regeneration varies greatly. Humans can recover from blood loss as well as damage to tissues like bone and liver. Yet damage to the heart and brain cannot be reversed, resulting in scaring. Thus, there is a great interest in understanding the molecular mechanisms of naturally occurring regeneration and to apply this knowledge to repair human organs. During regeneration, injury-activated immune cells induce wound healing, extracellular matrix remodeling, migration, dedifferentiation and/or proliferation with subsequent differentiation of somatic or stem cells. An anti-inflammatory response stops the regenerative process, which ends with tissue remodeling to achieve the original functional state. Notably, many of these processes are associated with enhanced glycolysis. Therefore, peroxisome proliferator-activated receptor (PPAR) β/δ—which is known to be involved for example in lipid catabolism, glucose homeostasis, inflammation, survival, proliferation, differentiation, as well as mammalian regeneration of the skin, bone and liver—appears to be a promising target to promote mammalian regeneration. This review summarizes our current knowledge of PPARβ/δ in processes associated with wound healing and regeneration.

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A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism

Cited by 12 publications

References 47 publications

Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

3,2′-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells

PPARβ/δ: Linking Metabolism to Regeneration

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