Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation

Aoki, Masayoshi; Aoki, Hiroaki; Mukhopadhyay, Partha; Tsuge, Takuya; Yamamoto, Hirofumi; Matsumoto, Noriko; Toyohara, Eri; Okubo, Yuri; Ogawa, Rei; Takabe, Kazuaki

doi:10.3390/ijms20143381

Cited by 34 publications

(30 citation statements)

References 46 publications

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“…At this time, we do not yet know the biological consequences of this regulation in more complex setting, but there is reason to believe that they could be numerous. In fibroblasts, S1P signaling has been shown to increase wound healing in mice 45 , 46 . We speculate that the elevated O-GlcNAc levels in diabetes may attenuate S1P signaling with detrimental consequences for fibroblast biology in wound healing.…”

Section: Discussionmentioning

confidence: 99%

MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction

et al. 2020

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Many intracellular proteins are modified by N-acetylglucosamine, a posttranslational modification termed O-GlcNAc. This modification is found on serine and threonine side-chains and has the potential to regulate signaling pathways through interplay with phosphorylation. Here, we discover and characterize one such example. We find that O-GlcNAc levels control the sensitivity of fibroblasts to actin contraction induced by the signaling lipid sphingosine-1-phosphate (S1P), culminating in the phosphorylation of myosin light chain (MLC) and cellular contraction. Specifically, O-GlcNAc modification of the phosphatase subunit MYPT1 inhibits this pathway by blocking MYPT1 phosphorylation, maintaining its activity and causing the dephosphorylation of MLC. Finally, we demonstrate that O-GlcNAc levels alter the sensitivity of primary human dermal fibroblasts in a collagen-matrix model of wound healing. Our findings have important implications for the role of O-GlcNAc in fibroblast motility and differentiation, particularly in diabetic wound healing.

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Section: Discussionmentioning

confidence: 99%

MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction

et al. 2020

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“…We and others have repeatedly demonstrated that S1P plays a critical role in angiogenesis [ 10 , 11 , 12 , 17 , 19 , 20 , 40 , 41 , 42 ]. In agreement with our mechanistic model [ 12 ], elevation of SphK1 , suppression of sphingosine kinase 2 ( SphK2 ), elevation of SPNS2 and Sphingosine-1-phosphate kinase receptor-1 ( S1PR1 ), all of which work to export S1P and promote angiogenesis, were associated with high score tumors (all p < 0.001, Figure 1 E).…”

Section: Resultsmentioning

confidence: 99%

Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer

Oshi

Newman

Tokumaru

et al. 2020

IJMS

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Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer.

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“…Our group recently showed that topically applied sCA effectively transfects the wound bed in mice. 40 Wu et al. 18 also reported that if relatively large particles that contaminate sCA can be removed, the resulting purified sCA preparation is very safe in mice and monkeys.…”

Section: Discussionmentioning

confidence: 99%

Direct Delivery of Apatite Nanoparticle-Encapsulated siRNA Targeting TIMP-1 for Intractable Abnormal Scars

Aoki

Matsumoto

Dohi

et al. 2020

Molecular Therapy - Nucleic Acids

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Hypertrophic scars (HSs) and keloids are histologically characterized by excessive extracellular matrix (ECM) deposition. ECM deposition depends on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs). TIMP-1 has been linked to ECM degradation and is therefore a promising therapeutic strategy. In this study, we generated super carbonate apatite (sCA) nanoparticle-encapsulated TIMP-1 small interfering RNA (siRNA) (siTIMP1) preparations and examined the effect of local injections on mouse HSs and on ex vivo -cultured keloids. The sCA-siTIMP1 injections significantly reduced scar formation, scar cross-sectional areas, collagen densities, and collagen types I and III levels in the lesions. None of the mice died or exhibited abnormal endpoints. Apatite accumulation was not detected in the other organs. In an ex vivo keloid tissue culture system, sCA-siTIMP1 injections reduced the thickness and complexity of collagen bundles. Our results showed that topical sCA-siTIMP1 injections during mechanical stress-induced HS development reduced scar size. When keloids were injected three times with sCA-siTIMP1 during 6 days, keloidal collagen levels decreased substantially. Accordingly, sCA-siRNA delivery may be an effective approach for keloid treatment, and further investigations are needed to enable its practical use.

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Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation

Cited by 34 publications

References 46 publications

MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction

MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction

Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer

Direct Delivery of Apatite Nanoparticle-Encapsulated siRNA Targeting TIMP-1 for Intractable Abnormal Scars

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