The role of Notch signaling in diabetic endothelial progenitor cells dysfunction

Sukmawati, Dewi; Tanaka, Rica; Ito‐Hirano, Rie; Fujimura, Satoshi; Hayashi, Akira; Itoh, Seigo; Mizuno, Hiroshi; Daida, Hiroyuki

doi:10.1016/j.jdiacomp.2015.09.015

Cited by 12 publications

(9 citation statements)

References 51 publications

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“…Similar to our protein KDR expression data, it has been previously reported that the number of CD341/KDR1 cells is significantly lower in diabetic patients [8,31]. Diabetic EPCs are reported to have a VEGF-VEGFR signaling defect, and PCR data for murine EPCs show high VEGFR expression similar to our RT-qPCR data [32]. It is likely that decreased VEGF expression leads to an increase in expression of VEGFR-2 to compensate for the deficiency of VEGF signaling.…”

Section: Discussionsupporting

confidence: 90%

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells

Tanaka¹,

Masuda

Fujimura³

et al. 2018

Stem Cells Translational Medicine

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Autologous endothelial progenitor cell (EPC) therapy is commonly used to stimulate angiogenesis in ischemic repair and wound healing. However, low total numbers and functional deficits of EPCs make autologous EPC therapy ineffective in diabetes. Currently, no known ex vivo culture techniques can expand and/or ameliorate the functional deficits of EPCs for clinical usage. Recently, we showed that a quality‐quantity culture (QQc) system restores the vasculogenic and wound‐healing efficacy of murine diabetic EPCs. To validate these results and elucidate the mechanism in a translational study, we evaluated the efficacy of this QQc system to restore the vasculogenic potential of diabetic human peripheral blood (PB) CD34+ cells. CD34+ cells purified from PB of diabetic and healthy patients were subjected to QQc. Gene expression, vascular regeneration, and expression of cytokines and paracrine mediators were analyzed. Pre‐ or post‐QQc diabetic human PB‐CD34+ cells were transplanted into wounded BALB/c nude mice and streptozotocin‐induced diabetic mice to assess functional efficacy. Post‐QQc diabetic human PB‐CD34+ cell therapy significantly accelerated wound closure, re‐epithelialization, and angiogenesis. The higher therapeutic efficacy of post‐QQc diabetic human PB‐CD34+ cells was attributed to increased differentiation ability of diabetic CD34+ cells, direct vasculogenesis, and enhanced expression of angiogenic factors and wound‐healing genes. Thus, QQc can significantly enhance the therapeutic efficacy of human PB‐CD34+ cells in diabetic wounds, overcoming the inherent limitation of autologous cell therapy in diabetic patients, and could be useful for treatment of not only wounds but also other ischemic diseases. Stem Cells Translational Medicine 2018;7:428–438

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Section: Discussionsupporting

confidence: 90%

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells

Tanaka¹,

Masuda

Fujimura³

et al. 2018

Stem Cells Translational Medicine

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“…16 MiR-34a was reported to target Notch mRNA and exacerbate diabetic endothelial dysfunction 41 in rats. 50,51 Therefore, it is needed to investigate whether or not NOTCH mediates miR-34a's action on diabetic endothelial dysfunction by gene silencing/overexpression in future studies. However, more evidence has shown the negative regulatory effect of SIRT1 on NOTCH through deacetylation in ECs.…”

Section: Discussionmentioning

confidence: 99%

“…48,49 Moreover, numerous studies have demonstrated the pathogenic role of NOTCH in diabetic endothelial dysfunction. 50,51 Therefore, it is needed to investigate whether or not NOTCH mediates miR-34a's action on diabetic endothelial dysfunction by gene silencing/overexpression in future studies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

Wang

Tian

et al. 2019

J Cellular Molecular Medi

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Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)‐treated endothelial cells (ECs) were subjected to pifithrin‐α (PFT‐α)—a specific inhibitor of P53, or P53 ‐small interfering RNA (siRNA), both of which attenuated the HG‐induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT‐α or P53 ‐siRNA prohibited P53 acetylation, decreased microRNA‐34a (miR‐34a) level, leading to a dramatic increase in sirtuin 1 (SIRT1) protein level. Interestingly, the miR‐34a inhibitor (miR‐34a‐I) and PFT‐α increased SIRT1 protein level and alleviated the HG‐induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT‐α were completely abrogated by the miR‐34a mimic. In addition, SIRT1 inhibition by EX‐527 or Sirt1 ‐siRNA completely abolished miR‐34a‐I's protection against HG‐induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin‐induced diabetic mice, both PFT‐α and miR‐34a‐I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR‐34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR‐34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.

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“…Similarly, numerous researches have been confirmed a prohibitory effect of hyperglycemic environment on endothelial progenitor cells (EPCs) participation in tube‐like structures [Ingram et al, ]. Sukmavati and collaborators acclaimed that over‐activation of Notch‐1/Dll‐4/Jag‐1 signaling markedly reduced EPCs tubulogenesis in diabetic condition [Sukmawati et al, ]. The reasonable interaction between glucose and free fatty acid metabolism affected in vitro tubulogenesis in first trimester trophoblast cells as the introduction of these cells to a higher concentration of glucose disintegrated the generated tube‐like structures [Basak et al, ].…”

Section: Discussionmentioning

confidence: 99%

Type 2 Diabetes Inhibited Human Mesenchymal Stem Cells Angiogenic Response by Over‐Activity of the Autophagic Pathway

Rezabakhsh

Cheraghi

Nourazarian

et al. 2017

J of Cellular Biochemistry

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The current study aimed to address the impact of serum from type 2 diabetes patients on the angiogenic properties of human bone marrow mesenchymal stem cells and its relationship to autophagy signaling. Human primary stem cells were enriched and incubated with serum from diabetic and normal subjects for 7 days. Compared to data from the control group, diabetic serum was found to induce a higher cellular death rate (P < 0.001) and apoptotic changes (P < 0.01). We also showed that diabetic condition significantly abolished angiogenesis tube formation on Matrigel substrate, decreased cell chemotaxis (P < 0.01) in response to SDF-1α, and inhibited endothelial differentiation rate (P < 0.0001). Western blotting showed autophagic status by high levels of P62 (P < 0.0001), beclin-1 (P < 0.0001), and increase in LC3II/I ratio (P < 0.001). In vivo Matrigel plug assay revealed that supernatant conditioned media prepared from cells exposed to diabetic serum caused a marked reduction in the recruitment of VE-cadherin- (P < 0.01) and α-SMA-positive (P < 0.0001) cells 7 days after subcutaneous injection. PCR expression array analysis confirmed the overexpression of autophagy and apoptosis genes in cultured cells in response to a diabetic condition (P < 0.05). Using bioinformatic analysis, we noted a crosstalk network between DM2, angiogenesis, and autophagy signaling. DM2 could potently modulate angiogenesis by the interaction of IL-1β with downstream insulin receptor and upstream androgen receptor. Corroborating to data, diabetic serum led to abnormal regulation of P62 during the angiogenic response. These data demonstrate that diabetic serum decreased human mesenchymal stem cell angiogenic properties directly on angiogenesis pathways or by the induction of autophagy signaling. J. Cell. Biochem. 118: 1518-1530, 2017. © 2016 Wiley Periodicals, Inc.

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The role of Notch signaling in diabetic endothelial progenitor cells dysfunction

Cited by 12 publications

References 51 publications

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

Type 2 Diabetes Inhibited Human Mesenchymal Stem Cells Angiogenic Response by Over‐Activity of the Autophagic Pathway

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