Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Zheng, Xiaowei; Narayanan, Sampath; Sunkari, Vivekananda Gupta; Eliasson, Sofie; Botusan, Ileana Ruxandra; Grünler, Jacob; Catrina, Anca I.; Radtke, Freddy; Xu, Cheng; Zhao, Allan Z.; Ekberg, Neda Rajamand; Lendahl, Urban; Catrina, Sergiu‐Bogdan

doi:10.1073/pnas.1900351116

Cited by 66 publications

(48 citation statements)

References 65 publications

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“…Delta-like ligand 4 (DLL4), one of the ligands of Notch receptors, is predominantly expressed in the endothelial cells and has been shown to play a pivotal role in regulating tumor angiogenesis [38][39][40][41][42][43][44][45]. Some studies reveal a role for DLL4 in tumorigenesis in several cancers, including T acute lymphoblastic leukemia (T-ALL) [46], and glioblastoma [47] etc.…”

Section: Discussionmentioning

confidence: 99%

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Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

Wang

et al. 2020

Mol Cancer

102

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Background: Accumulating literatures have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Urothelial cancer associated 1 (UCA1) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the molecular mechanism of UCA1 in renal cancer is still needed to further explore. Methods: The relative expression level of UCA1 was determined by Real-Time qPCR in a total of 88 patients with urothelial renal cancer and in different renal cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of UCA1 and miR-182-5p on renal cancer cell proliferation, migration, apoptosis and tumorigenicity. Comprehensive transcriptional analysis, dual-luciferase reporter assay and western blot etc. were performed to explore the molecular mechanisms underlying the functions of UCA1. Results: In this study, we found that UCA1 was significantly up-regulated in renal cancer. Moreover, increased UCA1 expression was positively correlated with differentiation and advanced TNM stage. Further experiments demonstrated that knockdown of UCA1 inhibited malignant phenotypes and Notch signal path of renal cancer cells, and miR-182-5p was reverse function as UCA1. UCA1 functioned as a miRNA sponge to positively regulate the expression of Delta-like ligand 4(DLL4) through sponging miR-182-5p and subsequently promoted malignant phenotypes of renal cancer cells, thus UCA1 playing an oncogenic role and miR-182-5p as an antioncogenic one in renal cancer pathogenesis. Conclusion: UCA1-miR-182-5p-DLL4 axis is involved in proliferation and progression of renal cancer. Thus, this study demonstrated that UCA1 plays a critical regulatory role in renal cancer cell and UCA1 may serve as a potential diagnostic biomarker and therapeutic target of renal cancer.

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Section: Discussionmentioning

confidence: 99%

“…Some studies reveal a role for DLL4 in tumorigenesis in several cancers, including T acute lymphoblastic leukemia (T-ALL), and glioblastoma etc. [37][38][39][40][41][42][43][44][45][46][47]. DLL4 is one of the ligands of Notch 1.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

Wang

et al. 2020

Mol Cancer

102

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“…Although previous studies demonstrated that certain molecules are abnormally expressed in three cell types of skin under diabetic conditions, other studies indicated that some molecules were expressed differently and inconsistently by the three cell types. One study showed that exposure to high glucose (HG) was followed by increased expression of Notch intracellular domain in fibroblasts, microvascular endothelial cells, and keratinocytes (2). In addition, increased expression of MMP9 under hypoglycemic conditions has been detected not only in human skin fibroblasts and microvascular endothelial cells but also in keratinocytes (9,10).…”

Section: Introductionmentioning

confidence: 99%

High Glucose Causes Distinct Expression Patterns of Primary Human Skin Cells by RNA Sequencing

Zhang

Yang

et al. 2021

Front. Endocrinol.

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Diabetes-related skin problems represent the most common long-term complications in diabetes mellitus patients. These complications, which include diabetic dermopathy, diabetic blisters, necrobiosis lipoidica diabeticorum, and eruptive xanthomatosis, may dramatically impair patients’ quality of life and cause long-lasting disability. However, the cellular and molecular mechanisms linking diabetes-related hyperglycemia and skin complications are still incompletely understood. To assess the role of the various skin-cell types in hyperglycemia-induced skin disorders, we performed RNA sequencing-based transcriptome analysis, measuring gene expression patterns in biological replicates in normal- and high glucose-stimulated skin cells. Three primary human skin-cell types were examined, i.e., epidermal keratinocytes, dermal fibroblasts, and dermal microvascular endothelial cells. For each separate cell type, we identified gene expression. Comparing gene abundances and expression levels revealed that transcription profiles exhibit distinct patterns in the three skin-cell types exposed to normal (i.e., physiological) glucose treatment and high (i.e., supraphysiological) glucose treatment. The obtained data indicate that high glucose induced differential gene expression and distinct activity patterns in signaling pathways in each skin-cell type. We are adding these data to the public database in the hope that they will facilitate future studies to develop novel targeted interventions for diabetic skin complications.

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“…These previous studies suggest that high intracellular Notch pathway activity attenuates cellular activity of fibroblasts and are consistent with the findings of the current study. Interestingly, the inhibitory role of Notch pathway activation in modulating keratinocyte-, EC-, and macrophages-mediated diabetic wound healing has been reported ( Kimball et al, 2017 ; Zheng et al, 2019 ). These findings, along with ours, imply a general role of the Notch signaling in the regulation of the reparative responses of various types of cells in diabetic wound healing.…”

Section: Discussionmentioning

confidence: 99%

Notch1 signaling determines the plasticity and function of fibroblasts in diabetic wounds

Shao

Pastar

et al. 2020

Life Sci. Alliance

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Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin and non-diabetic wounds. Consistently, wound healing in the FSP-1+/−;ROSALSL-N1IC+/+ mouse, in which Notch1 is activated in fibroblasts, is delayed. Increased Notch1 activity in fibroblasts suppressed their growth, migration, and differentiation into myofibroblasts. Accordingly, significantly fewer myofibroblasts and less collagen were present in granulation tissues of the FSP-1+/−;ROSALSL-N1IC+/+ mice, demonstrating that high Notch1 activity inhibits fibroblast differentiation. High Notch1 activity in fibroblasts diminished their role in modulating the angiogenic response. We also identified that IL-6 is a functional Notch1 target and involved in regulating angiogenesis. These findings suggest that Notch1 signaling determines the plasticity and function of fibroblasts in wound healing and angiogenesis, unveiling intracellular Notch1 signaling in fibroblasts as potential target for therapeutic intervention in diabetic wound healing.

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Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Cited by 66 publications

References 65 publications

Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

High Glucose Causes Distinct Expression Patterns of Primary Human Skin Cells by RNA Sequencing

Notch1 signaling determines the plasticity and function of fibroblasts in diabetic wounds

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